Tuesday, December 30, 2014

Measuring missing heritability: Inferring the contribution of common variants

This recent paper from Eric Lander proposes an alternative to GCTA. There is an interesting change in tone vis a vis an earlier paper with Zuk. Instead of speculating about explanations of missing heritability (beyond the existence of yet undiscovered common variants of small effect), the paper focuses on the claim that REML/GCTA underestimates the heritability due to common variants in case-control designs. The proposed alternative methodology, called phenotype correlation–genetic correlation (PCGC) regression, estimates heritability by directly regressing phenotype correlation vs genotype correlation across all pairs in the sample. (This is how I usually explain the concept behind GCTA when I don't want to get into details of REML, LMMs, etc.)

Personally, I am not especially concerned about the precise value of heritability estimates from REML/GCTA or PCGC, as there are significant uncertainties that go beyond the simple additive model assumed in both of these methods (e.g., due to nonlinear genetic architecture). For me it is sufficient that the results of both are consistent with classical estimates from twin and adoption studies, and yield h2 ~ 0.5 or higher for many interesting traits.
Measuring missing heritability: Inferring the contribution of common variants (PNAS)

D. Golan, E. Lander and S. Gosset

Studies have identified thousands of common genetic variants associated with hundreds of diseases. Yet, these common variants typically account for a minority of the heritability, a problem known as “missing heritability.” Geneticists recently proposed indirect methods for estimating the total heritability attributable to common variants, including those whose effects are too small to allow identification in current studies. Here, we show that these methods seriously underestimate the true heritability when applied to case–control studies of disease. We describe a method that provides unbiased estimates. Applying it to six diseases, we estimate that common variants explain an average of 60% of the heritability for these diseases. The framework also may be applied to case–control studies, extreme-phenotype studies, and other settings.
From the conclusion:
... Our results suggest that larger CVASs [GWAS] will identify many additional common variants related to common diseases, although many additional common variants likely still will have effect sizes that fall below the limits of detection given practically achievable sample sizes. Still, common variants clearly will not explain all heritability. As discussed in the first two papers in this series (2,3), rare genetic variants and genetic interactions likely will make important contributions as well. Fortunately, advances in DNA sequencing technology should make it possible in the coming years to carry out comprehensive studies of both common and rare genetic variants in tens (and possibly hundreds) of thousands of cases and controls, resulting in a fuller picture of the genetic architecture of common diseases.
Hopefully, more papers like this one will help the field of genomics to update its priors: the most reasonable hypothesis concerning "missing heritability" is simply that larger sample size is required to find the many remaining alleles of small effect. Fisher's infinitesimal model will turn out to be a good first approximation for most human traits. See also Additivity and complex traits in mice.

Sunday, December 28, 2014

Power and paranoia in Silicon Valley

Plenty of fear and loathing of the nerd rapture backed by powerful VCs in this Harper's article. Ungated version.

Discussed in depth at LessWrong.
... Be explorers; take advantage of this vast new landscape that’s been opened up to us in this time and this place; and bear the torch of applied rationality like brave explorers. And then, like, keep in touch by email.” The workshop attendees put giant Post-its on the walls expressing the lessons they hoped to take with them. A blue one read RATIONALITY IS SYSTEMATIZED WINNING. Above it, in pink: THERE ARE OTHER PEOPLE WHO THINK LIKE ME. I AM NOT ALONE.

... I talked to one of my roommates, a Google scientist who worked on neural nets. The CFAR workshop [[ Center For Applied Rationality ]] was just a whim to him, a tourist weekend. “They’re the nicest people you’d ever meet,” he said, but then he qualified the compliment. “Look around. If they were effective, rational people, would they be here? Something a little weird, no?”

... Were they really going to save the world? From what? “Imagine there is a set of skills,” he said. “There is a myth that they are possessed by the whole population, and there is a cynical myth that they’re possessed by 10% of the population. They’ve actually been wiped out in all but about one person in three thousand.” It is important, Vassar said, that his people, “the fragments of the world,” lead the way during “the fairly predictable, fairly total cultural transition that will predictably take place between 2020 and 2035 or so.” We pulled up outside the Rose Garden Inn. He continued: “You have these weird phenomena like Occupy where people are protesting with no goals, no theory of how the world is, around which they can structure a protest. Basically this incredibly, weirdly, thoroughly disempowered group of people will have to inherit the power of the world anyway, because sooner or later everyone older is going to be too old and too technologically obsolete and too bankrupt. The old institutions may largely break down or they may be handed over, but either way they can’t just freeze. These people are going to be in charge, and it would be helpful if they, as they come into their own, crystallize an identity that contains certain cultural strengths like argument and reason.” I didn’t argue with him, except to press, gently, on his particular form of elitism. His rationalism seemed so limited to me, so incomplete. “It is unfortunate,” he said, “that we are in a situation where our cultural heritage is possessed only by people who are extremely unappealing to most of the population.” That hadn’t been what I’d meant. I had meant rationalism as itself a failure of the imagination. “The current ecosystem is so totally fucked up,” Vassar said. “But if you have conversations here” -- he gestured at the hotel -- “people change their mind and learn and update and change their behaviors in response to the things they say and learn. That never happens anywhere else.” ...
Makes me wish I still lived in the Bay Area :-)  My MIRI interview.

Howard French: China's Second Continent

Another recommendation: China's Second Continent: How a Million Migrants Are Building a New Empire in Africa by Howard French (a former Africa and China correspondent for the NY Times). This is real boots on the ground reporting. French (a Mandarin speaker) spent time with Chinese immigrants across Africa, from small shopkeepers and farmers to real estate moguls and high government officials. Reviews: WSJ, NYTimes.

An interview with French on the Sinica podcast.
Exactly how exploitative are Chinese development activities on the African continent? What exactly is motivating the various resources-for-development deals inked by African governments over the last decade, and what strategies are these governments now adopting in the face of power imbalances with China? What is driving the mass migration of Chinese workers to the African continent, and why does everyone from Senegal seem to come from Henan?

This week on Sinica, we ask these questions and many more as Kaiser Kuo and Jeremy Goldkorn are joined in conversation with Howard French. If you've spent a while in China, you may have heard of Howard as the author of a well-known book on Shanghai's architectural legacy, and lecturer on the subject. What you may not know is that he is also an expert on African development, and the new author of China's Second Continent: How a Million Migrants Are Building a New Empire in Africa.

I wonder whether French is familiar with Galton's famous (and very politically incorrect; written in 1873) letter Africa for the Chinese. In some respects Galton is eerily prescient.
... The Chinaman is a being of another kind, who is endowed with a remarkable aptitude for a high material civilization. He is seen to the least advantage in his own country, where a temporary dark age still prevails, which has not sapped the genius of the race, though it has stunted the development of each member of it, by the rigid enforcement of an effete system of classical education which treats originality as a social crime. All the bad parts of his character, as his lying and servility, spring from timidity due to an education that has cowed him, and no treatment is better calculated to remedy that evil than location in a free settlement. The natural capacity of the Chinaman shows itself by the success with which, notwithstanding his timidity, he competes with strangers, wherever he may reside. The Chinese emigrants possess an extraordinary instinct for political and social organization; they contrive to establish for themselves a police and internal government, and they give no trouble to their rulers so long as they are left to manage those matters by themselves. They are good-tempered, frugal, industrious, saving, commercially inclined, and extraordinarily prolific. They thrive in all countries, the natives of the Southern provinces being perfectly able to labor and multiply in the hottest climates. ...

... The pressure of population in China is enormous, and its outflow is great and increasing. There is no lack of material for a suitable immigration into Africa. ... The Chinese have a land hunger, as well as a love for petty traffic, and they would find a field in which to gratify both of these tastes on the East African Coast. There are many Chinese capitalists resident in foreign parts who might speculate in such a system and warmly encourage it. ...

Belonging and Genocide: Hitler's Community, 1918-1945

I recommend this podcast interview with Thomas Kuhne, author of Belonging and Genocide: Hitler's Community, 1918-1945.

Kuhne claims that no German soldier ever faced court martial for refusing to kill a civilian. He estimates that (only?) about 200k German soldiers in total were involved in the killing of Jews or other civilians. But by the end of the war every German who wanted to know about "crimes in the east" could easily find out. This last observation is supported by letters and diary entries of ordinary people. Matters of national guilt or conscience weighed heavily on soldiers and ordinary Germans by the end of the war, Kuhne claims.

Kuhne makes interesting observations about the male social hierarchy within military units. Those who refused to carry out Nazi orders against civilians were regarded as weaklings, but were not subjected to direct reprisal.
There are two means to unite a people — common ideals and common crime.
—Adolf Hitler, Party Leader, Munich, 1923

If this Jewish business is ever avenged on earth, then have mercy on us Germans.
—Major Trapp, Police Officer, Poland, 1942

For there is a great, bright aspect to this war: namely a great comradeship.
—Adolf Hitler, Reich Chancellor, Berlin, 1942

We Germans are the nation that has gone for this war enthusiastically and will have to bear the consequences.
—Franz Wieschenberg, Wehrmacht Private, Eastern Front, 1944

To stick together and to fight side by side and be wounded side by side, that’s our wish.
—Kurt Kreissler, Wehrmacht NCO, Germany, 1945

UFC 182: Jones vs Cormier

This will be one for the ages. I think Cormier can get inside on the taller Jones. We'll see Jones fighting off his back for the first time. I wonder what his guard is like.

In the last video Cormier is shown wrestling with Russian Olympic gold medalist Khajumurad Gatsalov.

Wednesday, December 24, 2014

Peace on Earth, Good Will to Men 2014

For years, when asked what I wanted for Christmas, I've been replying: peace on earth, good will toward men :-)

No one ever seems to recognize that this comes from the bible, Luke 2.14 to be precise!

Linus said it best in A Charlie Brown Christmas:
And there were in the same country shepherds abiding in the field, keeping watch over their flock by night.

And, lo, the angel of the Lord came upon them, and the glory of the Lord shone round about them: and they were sore afraid.

And the angel said unto them, Fear not: for, behold, I bring you good tidings of great joy, which shall be to all people.

For unto you is born this day in the city of David a Saviour, which is Christ the Lord.

And this shall be a sign unto you; Ye shall find the babe wrapped in swaddling clothes, lying in a manger.

And suddenly there was with the angel a multitude of the heavenly host praising God, and saying,

Glory to God in the highest, and on earth peace, good will toward men.

Merry Christmas!
In preparation for the new year:
Marcus Aurelius

Or does the bubble reputation distract you? Keep before your eyes the swift onset of oblivion, and the abysses of eternity before us and behind; mark how hollow are the echoes of applause, how fickle and undiscerning the judgments of professed admirers, and how puny the arena of human fame. For the entire earth is but a point, and the place of our own habitation but a minute corner in it; and how many are therein who will praise you, and what sort of men are they?

Tuesday, December 23, 2014

Gender trouble in the valley

This NYTimes article looks at the gender disparity in technology career success within the Stanford class of 1994.
NYTimes: In the history of American higher education, it is hard to top the luck and timing of the Stanford class of 1994, whose members arrived on campus barely aware of what an email was, and yet grew up to help teach the rest of the planet to shop, send money, find love and navigate an ever-expanding online universe. ...
I found this reader comment to be realistic -- it is consistent with my own experience both as a parent and as a startup founder.
tiddle nyc

I've been in tech field for some years now. Being a working mother, with two kids (one boy, one girl), this subject hits close to home.

When I first started, there were more women in the ranks than it is now. I never experienced any sexism or discrimination in workplace, nor did I ever feel pushed aside. But I have to say this to my fellow female peers, in order to get ahead, you have to stay in the field. Dropping out or even scaling back will not help, and you can't blame others for not entrusting you with high profile projects because you might not be here next week.

Naturally it helps to have a spouse who share chores and childrearing, rather than having the woman/mother/wife to have-it-all, but really do-it-all which is practically impossible. That's how we stay the course and allow a pathway for younger generations of female to move up the ranks.

Looking at my kids - and we raise them to have the same aspirations, ambitions, and aggressiveness - there is indeed certain nature-vs-nurture difference. Justified or not, my son is almost always over-confident in his ability in all situations whereas my daughter is more circumspect and tentative (even if she's more than capable). It takes a lot more encouragement to prompt my daughter to be aggressive, whereas my son naturally does it on his own. As I look around all those in fields like VC and startups, I see mirrors of how men and women behavior.

This article doesn't surprise me.
See also Gender differences in preferences, choices, and outcomes: SMPY longitudinal study. A longitudinal study of mathematically precocious men and women (SMPY) showed significant gender differences in life and career preferences:
... According to the results, SMPY men are more concerned with money, prestige, success, creating or inventing something with impact, etc. SMPY women prefer time and work flexibility, want to give back to the community, and are less comfortable advocating unpopular ideas. Some of these asymmetries are at the 0.5 SD level or greater. Here are three survey items with a ~ 0.4 SD or more asymmetry:

# Society should invest in my ideas because they are more important than those of other people.

# Discomforting others does not deter me from stating the facts.

# Receiving criticism from others does not inhibit me from expressing my thoughts.

I would guess that Silicon Valley entrepreneurs and leading technologists are typically about +2 SD on each of these items! One can directly estimate M/F ratios from these parameters ...

The anecdote below about serial entrepreneur David Sacks is amusing:
NYTimes: ... Mr. Sacks almost wasn't hired because of doubts that he could work well with others; during his job interview, he put the chief financial officer on notice that his own job would be totally different once Mr. Sacks arrived, Mr. Thiel remembered. But his lack of social grace became an asset, according to Mr. Thiel and other former colleagues. He did not waste time on meetings that seemed pointless, and he bluntly insisted that the engineers whittle an eight-page PayPal registration process down to one.

Everyone knew Mr. Sacks was politically conservative, but in the office, he was less bombastic. He had become a manager, he said in an interview, and did not want to hurt the cohesion of his team. But he and Mr. Thiel now had a setting in which to try out their ideas about diversity and meritocracy. 'In the start-up crucible, performing is all that matters,' Mr. Sacks wrote about that time. He wanted to give all job applicants tests of cognitive ability, according to his colleague Keith Rabois, and when the company searched for a new chief executive, one of the requirements was an I.Q. of 160 -- genius level.

The goal was 'pure meritocracy,' said Amy Klement, one of a small number of women to rise high within the organization. She and other women called Mr. Sacks an effective, relentless, generous boss. But some also wondered how comfortable the men running the company were around them. Lauri Schultheis said that when she interviewed to be PayPal's office manager, and its first female employee -- before even Mr. Sacks arrived -- an engineer asked her, 'Does this mean I have to stop looking at porn? ...

Monday, December 22, 2014

Quantum GDP

"It's been only half jokingly said that today a third of GDP is attributable to quantum mechanics," -- former Lockheed CEO Norm Augustine.
I've heard the one third or 30% of GDP figure from time to time, but have never seen a detailed analysis. A list of modern technologies that arose from quantum mechanics would include: transistors, microprocessors, lasers, sophisticated chemistry and materials science, nuclear energy, memory chips, hard drive storage, LEDs, LCD displays, etc. These certainly account for a significant fraction of GDP.

Estimates of expenditures on communications and information technology alone in developed countries are typically in the 5-10% GDP range, which provides a lower bound. While the actual figure may be less than 30% it is certainly substantial. See here for a history of physics contributions to information technologies.

The huge (but poorly understood) impact of quantum mechanics on modern life is an example of the tremendous long term impact of fundamental research. There is every reason to think that increased world research expenditures would enhance productivity and quality of life, with very high ROI. However, there is little careful thinking about the "right" level of research investment as a fraction of GDP. Instead, we get:

Perhaps the most amazing aspect of the history of quantum mechanics is not its technological and practical impact, but rather how it led to deep changes in how we think about the universe. See, e.g., Two slit experimentBell and GHZWeinberg on quantum foundations, and On the origin of probability in quantum mechanics.

Early pioneers doubted whether humans were smart enough to understand quantum physics:
[Wigner] Until 1925, most great physicists, including Einstein and Planck, had doubted that man could truly grasp the deepest implications of quantum theory. They really felt that man might be too stupid to properly describe quantum phenomena. ... the men at the weekly colloquium in Berlin wondered "Is the human mind gifted enough to extend physics into the microscopic domain ...?" Many of those great men doubted that it could.
Quantum mechanics, which made possible the modern age, is nevertheless only understood by at most a fraction of a percent of the population. See also Psychometric thresholds for physics and mathematics, Chomsky: genetic barriers to scientific progress, and Beyond Human Science.
Beyond Human Science: [This Ted Chiang short story envisions a future in which science has become the province of genetically enhanced "metahumans" -- leaving non-enhanced humans to gape from the sidelines.]

... imagine if research offered hope of a different intelligence-enhancing therapy, one that would allow individuals to gradually "up-grade" their minds to a metahuman-equivalent level. Such a therapy would offer a bridge across what has become the greatest cultural divide in our species' history ...

We need not be intimidated by the accomplishments of metahuman science. We should always remember that the technologies that made metahumans possible were originally invented by humans, and they were no smarter than we.

Saturday, December 13, 2014

Preimplantation genetic diagnosis and screening using next generation sequencing

This BGI study reports pre-implantation sequencing of hundreds of blastocysts. 42 ongoing pregnancies were achieved, with 24 babies born thus far.
Clinical outcome of preimplantation genetic diagnosis and screening using next generation sequencing

Next generation sequencing (NGS) is now being used for detecting chromosomal abnormalities in blastocyst trophectoderm (TE) cells from in vitro fertilized embryos. However, few data are available regarding the clinical outcome, which provides vital reference for further application of the methodology. Here, we present a clinical evaluation of NGS-based preimplantation genetic diagnosis/screening (PGD/PGS) compared with single nucleotide polymorphism (SNP) array-based PGD/PGS as a control.

A total of 395 couples participated. They were carriers of either translocation or inversion mutations, or were patients with recurrent miscarriage and/or advanced maternal age. A total of 1,512 blastocysts were biopsied on D5 after fertilization, with 1,058 blastocysts set aside for SNP array testing and 454 blastocysts for NGS testing. In the NGS cycles group, the implantation, clinical pregnancy and miscarriage rates were 52.6% (60/114), 61.3% (49/80) and 14.3% (7/49), respectively. In the SNP array cycles group, the implantation, clinical pregnancy and miscarriage rates were 47.6% (139/292), 56.7% (115/203) and 14.8% (17/115), respectively. The outcome measures of both the NGS and SNP array cycles were the same with insignificant differences. There were 150 blastocysts that underwent both NGS and SNP array analysis, of which seven blastocysts were found with inconsistent signals. All other signals obtained from NGS analysis were confirmed to be accurate by validation with qPCR. The relative copy number of mitochondrial DNA (mtDNA) for each blastocyst that underwent NGS testing was evaluated, and a significant difference was found between the copy number of mtDNA for the euploid and the chromosomally abnormal blastocysts. So far, out of 42 ongoing pregnancies, 24 babies were born in NGS cycles; all of these babies are healthy and free of any developmental problems.

This study provides the first evaluation of the clinical outcomes of NGS-based pre-implantation genetic diagnosis/screening, and shows the reliability of this method in a clinical and array-based laboratory setting. NGS provides an accurate approach to detect embryonic imbalanced segmental rearrangements, to avoid the potential risks of false signals from SNP array in this study.


For those that can read Chinese, the journal Remembrance is archived here.

My father intended to take a sabbatical at Tsinghua University in Beijing when I was in grade school, but reconsidered it because of the craziness of the Cultural Revolution. I recall going with my mom and brother to get a passport photo taken in downtown Ames. Instead, we ended up at the University of Chicago, where my dad worked with another fluid dynamicist interested in vortices and tornadoes. My brother and I knew nothing about the Cultural Revolution, despite my dad's occasional comments. But we did realize we weren't in Iowa anymore when we saw the half dozen locks and iron bar on the door of our Hyde Park apartment in Chicago.
NY Review of Books: ... Besides Remembrance, China has roughly half a dozen other samizdat publications that explore the past through accounts of personal experience, including Scars of the Past (Wangshi Weihen), Annals of the Red Crag (Hongyan Chunqiu), and Yesterday (Zuotian). In addition, there are a growing number of underground documentary films, including some that send students to collect oral histories in villages that suffered during the Great Leap Famine or the Cultural Revolution.

One Saturday this spring, several of Remembrance’s regular writers stopped by the Tiantongyuan apartment for a pot of Pu’er tea and a chat with the journal’s cofounder, the retired film historian Wu Di. As they arrived, Wu leaned back in his chair and gave a running commentary on each. Among them were a computer data specialist at a technical university (“the greatest specialist on Lin Biao!”), an editor of the Communist Party’s flagship newspaper People’s Daily (“obviously he has to keep a low profile”), and a befuddled professor who had to call Wu three times to get directions (“what an egghead—he knows everything about violence in the Cultural Revolution but doesn’t know how to hail a gypsy cab”).

... Yet the memories of his youth stayed with him. He knew he had witnessed history and spent the 1980s carefully writing down what he’d heard, corroborating information with eyewitnesses. A fresh finding was the degree of ethnic hatred that underlay the violence. Official figures show that during the Cultural Revolution in Inner Mongolia 22,900 died and 790,000 were imprisoned, but there was no atonement and no discussion of the fact that most of the killers were Chinese or that the victims overwhelmingly were Mongolians. Wu’s conclusion was that this unresolved era continues to underlie ethnic tensions in the region.

But the manuscript was unpublishable and there was no Remembrance to get even the gist of it published in China. It lay in Wu’s desk drawer, a fading memory of the windswept Mongolian steppes. ...

... According to arcane rules that everyone accepts but whose origins no one knows, China’s public security classifies e-mails to fewer than two hundred people as a private distribution list; anything more is a publication, which means censorship and oversight. So officially, Remembrance’s writers are just people interested in history sending out an e-mail every once in a while to interested friends. It’s not their fault if Remembrance somehow reaches many of China’s educated elite, and is avidly read and collected by researchers abroad. Forwarding is beyond Wu’s control.

Outside, we could hear the men arguing. Their voices rose, until the discussion sounded almost angry; one man seemed to be shouting. The topic was the apologies made to victims of the Cultural Revolution, which had caused much debate in China’s social media in 2013 and 2014. The group could not agree whether it was a good thing or not. I prepared to go over and listen in. Dai looked up.

“They get heated, but it’s a chance for a release. They teach at universities but can’t teach this to their students. Think about that.”

Sunday, December 07, 2014

Feynman Lectures: Epilogue

The full text of The Feynman Lectures is now available online. These lectures were originally delivered to satisfy the physics requirement for first and second year students at Caltech. Legend has it that as the lectures went on, fewer and fewer undergraduates were seen in attendance, with their places taken by graduate students and even members of the faculty! In his epilogue, Feynman notes that only a few dozen students (out of a Caltech cohort of perhaps 200) were able to fully appreciate the material as it was delivered. Nevertheless, the lectures have been a resource for the physics community ever since.

When I was a high school student I took advanced physics courses at the local university. One of my professors suggested I look at the Feynman lectures for more challenging material. I ordered a set (paperback, with red covers) through the university bookstore -- I think they cost $30 in 1982. Years later I obtained a commemorative hardcover set (blue) which sits on my shelf even now.
Feynman's Epilogue

Well, I've been talking to you for two years and now I'm going to quit. In some ways I would like to apologize, and other ways not. I hope — in fact, I know — that two or three dozen of you have been able to follow everything with great excitement, and have had a good time with it. But I also know that “the powers of instruction are of very little efficacy except in those happy circumstances in which they are practically superfluous.” So, for the two or three dozen who have understood everything, may I say I have done nothing but shown you the things. For the others, if I have made you hate the subject, I'm sorry. I never taught elementary physics before, and I apologize. I just hope that I haven't caused a serious trouble to you, and that you do not leave this exciting business. I hope that someone else can teach it to you in a way that doesn't give you indigestion, and that you will find someday that, after all, it isn't as horrible as it looks.

Finally, may I add that the main purpose of my teaching has not been to prepare you for some examination—it was not even to prepare you to serve industry or the military. I wanted most to give you some appreciation of the wonderful world and the physicist's way of looking at it, which, I believe, is a major part of the true culture of modern times. (There are probably professors of other subjects who would object, but I believe that they are completely wrong.)

Perhaps you will not only have some appreciation of this culture; it is even possible that you may want to join in the greatest adventure that the human mind has ever begun.
What does Feynman mean by the true culture of modern times? Not mincing words, he refers to the greatest adventure that the human mind has ever begun! None can claim themselves an educated thinker or intellectual without mastery of a significant portion of the material in these lectures.

The figure below is from book III chapter 01: Quantum behavior

Friday, December 05, 2014

Dept. of Physicists Can Do Stuff: Ashton Carter

Secretary of Defense nominee Ashton B. Carter on his education and early career in theoretical physics. His Wikipedia entry says he did postdocs at Rockefeller University and MIT.
... when I rather unexpectedly was accepted into a good college, Yale, I was determined to make the most of it. I disdained the “preppies” and other privileged students who seemed to regard college as an opportunity to enjoy freedom at long last. I was an intensely serious student, what would probably be called today a “grind.”

At Yale I ended up pursuing two entirely different majors – physics and medieval history. There was no relationship between them in my mind except that both fascinated me. I liked dusty archives, learning to decipher manuscripts in medieval script, and learning all the languages necessary to read the primary and secondary historical literature, especially Latin. I wrote a senior thesis on the use of Latin by contemporary monastic writers to describe the vibrant world of 12th century Flanders in which they lived. I also enjoyed English legal history and the foundations of the Common Law as established in the 11th through 13th centuries. I also did a lot of work on the hagiography of Saint Denis, patron saint of the French monarchy during its formative period in the 9th century.

Physics was entirely different: clean and modern, logical and mathematical. I was lucky enough to be asked by a professor to assist him on an experiment in elementary particle physics at the then-new Fermilab outside of Chicago, home of the world’s largest particle accelerator. I would fly back and forth from New Haven to Chicago, feeling very serious and very important. We were involved in the search for the quark, a sub-atomic particle then only theorized. I eventually wrote my senior thesis, which was later published, on the “charmed quark.”

As far as course choice was concerned, I had no interest in between the extremes of medieval history (history, language, philosophy) on the one hand, and science (physics, chemistry, mathematics) on the other. It may sound shocking to Kennedy School students, but I have taken exactly zero social science courses in my entire life. My arrogant view at the time was that life would eventually teach me political science, sociology, psychology, and even economics, but it would never teach me linear algebra or Latin. It seemed best to get my tuition’s worth from the other topics and get my social science for free!

The end of college brought the usual crisis of what to do next. Such a bimodal distribution of training and interests made the problem more acute. The default solution was to go to medical school, since my father was a physician and I had worked in hospitals back in Philadelphia.

Fortunately, I was rescued from this dilemma by the awarding of a Rhodes scholarship, entitling me to free study at Oxford University. Many Rhodes scholars pursue a second Bachelors degree or a Masters degree at Oxford, but I was still a man in a hurry. I decided I would use the free funding to get my doctorate in theoretical physics. Oxford did not have enough money to have world class experimental facilities in elementary particle physics, but it had a great theoretical physics department. All you need for theoretical physics is a pencil and paper and the ability to sit for hours of intense concentration with a page of equations in front of you. I worked on the theory of quantum chromodynamics, the quantum field theory then postulated to explain the behavior of nuclear reactions and the structure of the sub-atomic zoo of particles. Unfortunately, it was a mathematical theory so complex that its equations could not be solved. I found a way to solve its equations in certain special circumstances, thus allowing it to be tested against experiments. Oxford was a very lively intellectual community. The expatriate Americans would spend long hours debating the topics of the day. Much of my otherwise lacking social science training occurred by osmosis in the pubs with Rhodes friends.

I had no doubt, however, that I wanted a career of thinking and writing in academia, then meaning theoretical physics. I therefore went back to the United States to start to climb the academic ladder in physics, beginning in the usual way with a postdoctoral appointment. I wrote several papers. The one of which I am proudest and which is still frequently cited, was on “time reversal invariance,” the proposition that the world could run backwards according to the same laws by which it runs forwards. While this may seem like a bizarre question to ask, such a symmetry in nature, if it exists, is actually a very fundamental property of our universe.

A Turning Point

I was happily building an academic career in theoretical physics when a serendipitous opportunity arose which opened up an entirely new vista for me. The year was 1979 and the Cold War was ratcheting up to a new peak of tension and the nuclear arsenals to new levels of potential destructiveness. My field of physics dated itself to the wartime Manhattan Project, and many of the senior figures in my field had long participated in the furtherance, but also in the control, of military technology. It was their view that their successor generations had a responsibility to remain involved in these matters. Thus, several senior figures in the field urged me to take a one-year leave of absence from theoretical physics to join a study team of scientists being assembled at the Congressional Office of Technology Assessment. ...
See also Physicists Can Do Stuff and Wandering Physicists.

CRISPR patent fight

Earlier CRISPR posts. MSU symposium with video. Patrick Hsu, one of the speakers (no relation), is from the Zhang lab.
Technology Review: Discovery of the Century?

There’s a bitter fight over the patents for CRISPR, a breakthrough new form of DNA editing.

... In April of this year, Zhang and the Broad won the first of several sweeping patents that cover using CRISPR in eukaryotes—or any species whose cells contain a nucleus (see “Broad Institute Gets Patent on Revolutionary Gene-Editing Method”). That meant that they’d won the rights to use CRISPR in mice, pigs, cattle, humans—in essence, in every creature other than bacteria.

The patent came as a shock to some. That was because Broad had paid extra to get it reviewed very quickly, in less than six months, and few knew it was coming. Along with the patent came more than 1,000 pages of documents. According to Zhang, Doudna’s predictions in her own earlier patent application that her discovery would work in humans was “mere conjecture” and that, instead, he was the first to show it, in a separate and “surprising” act of invention.

The patent documents have caused consternation. The scientific literature shows that several scientists managed to get CRISPR to work in human cells. In fact, its easy reproducibility in different organisms is the technology’s most exciting hallmark. That would suggest that, in patent terms, it was “obvious” that CRISPR would work in human cells, and that Zhang’s invention might not be worthy of its own patent.

What’s more, there’s scientific credit at stake. In order to show he was “first to invent” the use of CRISPR-Cas in human cells, Zhang supplied snapshots of lab notebooks that he says show he had the system up and running in early 2012, even before Doudna and Charpentier published their results or filed their own patent application. That timeline would mean he hit on the CRISPR-Cas editing system independently. In an interview, Zhang affirmed he’d made the discoveries on his own. Asked what he’d learned from Doudna and Charpentier’s paper, he said “not much.”

Not everyone is convinced. “All I can say is that we did it in my lab with Jennifer Doudna,” says Charpentier, now a professor at the Helmholtz Centre for Infection Research and Hannover Medical School in Germany. “Everything here is very exaggerated because this is one of those unique cases of a technology that people can really pick up easily, and it’s changing researchers’ lives. Things are happening fast, maybe a bit too fast.”

Thursday, December 04, 2014

Economics hegemony

Sociologists decry the ascendance of economics in the social sciences. See also Venn diagram for economics, Confessions of an economist, and Summers and Shleifer:
(Ellison, an anthropologist, was Dean of the Graduate School under Summers.)
Over lunch not long after Summers took over the presidency in 2001, Ellison said, Summers suggested that some funds should be moved from a sociology program to the Kennedy School, home to many economists and political scientists. ''President Summers asked me, didn't I agree that, in general, economists are smarter than political scientists, and political scientists are smarter than sociologists?" Ellison said. ''To which I laughed nervously and didn't reply."
The Superiority of Economists (Max Planck - Sciences Po discussion paper). Via Orgtheory. Krugman comments (highly recommended).
Abstract: In this essay, we investigate the dominant position of economics within the network of the social sciences in the United States. We begin by documenting the relative insularity of economics, using bibliometric data. Next we analyze the tight management of the field from the top down, which gives economics its characteristic hierarchical structure. Economists also distinguish themselves from other social scientists through their much better material situation (many teach in business schools, have external consulting activities), their more individualist worldviews, and in the confidence they have in their discipline’s ability to fix the world’s problems. Taken together, these traits constitute what we call the superiority of economists, where economists’ objective supremacy is intimately linked with their subjective sense of authority and entitlement. While this superiority has certainly fueled economists’ practical involvement and their considerable influence over the economy, it has also exposed them more to conflicts of interests, political critique, even derision.

... Some fifteen years ago, Richard Freeman (1999: 141) speculated on the origins of this conviction. His assessment was candid: "[S]ociologists and political scientists have less powerful analytical tools and know less than we do, or so we believe. By scores on the Graduate Record Examination and other criteria, our field attracts students stronger than theirs, and our courses are more mathematically demanding."
How Sociologists Made Themselves Irrelevant by Harvard sociologist Orlando Patterson. Via Scatterplot.
Chronicle: ... In closing, I would like to suggest two "smell tests" for all sociologists, but especially those engaged with the public sphere, when assessing their work. The first is the Garfinkel rule, mentioned earlier: Never treat your subjects as cultural dopes. If you find yourself struggling to explain away your subjects’ own reasoned and widely held account of what they consider important in explaining their condition, you are up to something intellectually fishy.

The second is this: If you end up with findings that have policy implications that you would never dream of advocating for yourself or your loved ones, be wary of them. A case in point: If you find that neighborhoods have no effects, you should be prepared to do the rational thing and go live in an inner-city neighborhood with its much cheaper real estate, or at least advise your struggling son or daughter searching for an apartment to save by renting there. If the thought offends you, then something stinks.
More fun links: The Econ con and Economics: is it science?

Wednesday, December 03, 2014

Bitcoin and the Blockchain

This looks like an interesting meeting. Maybe I'll see you there!

See also Ethereum.
O'Reilly: Bitcoin has spawned a lot of hype, a little apprehension, and plenty of confusion. But the blockchain behind bitcoin is a fundamental technological breakthrough. It has the potential to disrupt a wide range of industries and business practices—from fairly obvious potential financial services and retail industry disruptions to less apparent, but equally transformative, disruptions in areas such as micro-payments, contracts, and governmental services.

15 sessions will provide a coherent overview of the bitcoin and blockchain world, mapping out the challenges and opportunities, covering vital issues like cryptocurrency security and compliance, payments, venture capital, smart contracts, and the future of bitcoin.

Tuesday, December 02, 2014

Go B1G!

At the B1G annual meeting of research VPs. Beautiful B1G building near O'Hare paid for by big time sports.

But note the academic pride!


Monday, December 01, 2014

Cows, clones, and genomic selection

Via Gwern. See also Genomic Prediction: No Bull and It's all in the gene: cows.
National Geographic: ... The ideal rib eye in the American market is a marriage of opposites: It's richly marbled with internal fat to give it flavor, but it has only a thin layer of the back fat that no one wants. In the parlance of the U.S. Department of Agriculture, it's both "prime" and "yield grade 1." Cows that produce such beef are rarer than nose tackles who are great dancers. Only three carcasses in 10,000 make the grade.

But that night in the packing plant, Lawrence watched two go by in close succession—it was like being struck twice by lightning, he said, but in a good way. He pulled out his cell phone and called Dean Hawkins, the head of the animal sciences department at WTAMU. "It's time we cloned one of these things," he said.

... Though it's more expensive, there's a way to spare both cow and rancher the experience of artificial insemination: in vitro fertilization, or IVF. It's 90 percent of Trans Ova's business now, Crow says. The company does about 20,000 cattle IVF procedures a year, including 15 or 20 on the best cows at 44 Farms. ...

"We had a female in our herd—a foundation female," Slattery recalls. "She's deceased now. She lived to 13 years old, and she was very fertile. She had over a hundred progeny—well over a million dollars' worth of progeny in her lifetime. And it never really affected her. She had a wonderful life."

These days 44 Farms has a good idea that it has found such a prizewinner even before she has offspring, because the farm tests its calves' DNA when they're six months old. Just a couple drops of blood taken from the thin skin under the tail suffice. From that blood, Zoetis, a subsidiary of Pfizer, can determine how the animal compares with other Angus cattle at 50,000 points in the genome where Angus cattle are known to vary.

It's unclear what specific effect those individual mutations, or the genes they're part of, have on the animal. But by gathering data on thousands of Angus, Zoetis has established statistical correlations between each variation and traits that cattlemen care about—traits such as birth weight, weaning weight, marbling, and so on. The test assigns the animal a genetic score on each trait.

For the past five years 44 Farms has been using those scores to select animals to breed—and the results are in the beef, Slattery says. Though it's primarily a seed stock producer, 44 Farms also markets its own 44 Steaks to consumers online and to fancy restaurants. Since the farm began using genomic testing, it has seen a 20 percent increase in the number of carcasses that are graded prime or choice, the USDA's second-best grade for beef. Such carcasses fetch premiums of up to $500 a head. "It's absolutely huge," Slattery says.

There's an environmental upside too. The 44 Farms cattle are fattened at a feed yard in Hereford, Texas, but 44 Farms retains ownership of them—and they're given no hormones, antibiotics, or other additives. And thanks to the improved genetics of its herd, it no longer has to fatten them to 1,400 pounds to get meat that has prime or choice marbling. It's slaughtering them at 1,250 pounds, saving more than a month's worth of feed.

Tuesday, November 25, 2014

Homo Sapiens 2.0: Genetic Enhancement and the Future of Humanity

A discussion at the 92nd street Y in NYC, Nov. 24 2014.
Moderator Jamie Metzl is joined by George Church, Professor of Genetics at Harvard Medical School, Columbia University bioethicist Robert Klitzman, New York Stem Cell Foundation Co-Founder and CEO Susan Solomon, and Princeton Professor of Molecular Biology and Public Policy Lee Silver to discuss the opportunities and challenges of human genetic engineering, among the most important issues of the coming millennia.

Here's a link in case the embedded player doesn't work: http://92yondemand.org/homo-sapiens-2-0-genetic-enhancement-future-humanity/#sthash.YuscIir9.dpuf

More from Jamie Metzl.

Sunday, November 23, 2014

Citizenfour and Sisu

NYBooks: ... In an interview about Citizenfour with the New Yorker reporter Jane Mayer, Snowden has said that his action seemed to him necessary because the American officials charged with the relevant oversight had abdicated their responsibility. He meant that President Obama, Attorney General Eric Holder, and the intelligence committees in the House of Representatives and the Senate had utterly failed to guard against extraordinary abuses of the public trust under the pretext of national security. Nor had they undertaken the proper work of setting limits to government spying on Americans consistent with the spirit of the First Amendment and the letter of the Fourth Amendment.

...Snowden is often called a “fanatic” or a “zealot,” a “techie” or a “geek,” by persons who want to cut him down to size. Usually these people have not listened to him beyond snippets lasting a few seconds on network news. But the chance to listen has been there for many months, in two short videos by Poitras on the website of The Guardian, and more recently in a full-length interview by the NBC anchorman Brian Williams. The temper and penetration of mind that one can discern in these interviews scarcely matches the description of fanatic or zealot, techie or geek.

An incidental strength of Citizenfour is that it will make such casual slanders harder to repeat. Nevertheless, they are likely to be repeated or anyway muttered in semiprivate by otherwise judicious persons who want to go on with their business head-down and not be bothered. It must be added that our past politics give no help in arriving at an apt description of Snowden and his action. The reason is that the world in which he worked is new. Perhaps one should think of him as a conscientious objector to the war on privacy — a respectful dissident who, having observed the repressive treatment endured by William Binney, Thomas Drake, and other recent whistle-blowers, does not recognize the constitutional right of the government to put him in prison indefinitely and bring him to trial for treason. ...

What seems most remarkable in that hotel room in Hong Kong is Snowden’s freedom from anxiety. He is fearful, yes ... He knows that he is at risk of being subjected to “rendition” or worse. But there is no theatrical exaggeration here, and no trace of self-absorption. He has made his commitment and that is that. ...

... [Snowden] realizes that if he keeps his identity a secret, the government will rally all its powers and those of the media to convert the treacherous and hidden leaker into the subject of the story. His intuition is that the best way to counter such a distraction will be to make the story personal right away, but to render the personal element dry and matter-of-fact. He will do this in the most unobtrusive and ordinary manner. He will simply admit that he is the person and spell out the few relevant facts about his life and work.

The undeclared subject of Citizenfour is integrity—the insistence by an individual that his life and the principle he lives by should be all of a piece.
Sisu is a Finnish term loosely translated into English as strength of will, determination, perseverance, and acting rationally in the face of adversity. However, the word is widely considered to lack a proper translation into any other language. Sisu contains a long-term element; it is not momentary courage, but the ability to sustain an action against the odds. Deciding on a course of action and then sticking to that decision against repeated failures is sisu. It is similar to equanimity, except the forbearance of sisu has a grimmer quality of stress management than the latter.

Pessimism of the Intellect, Optimism of the Will.

Friday, November 21, 2014

Gender differences in preferences, choices, and outcomes: SMPY longitudinal study

The recent SMPY paper below describes a group of mathematically gifted (top 1% ability) individuals who have been followed for 40 years. This is precisely the pool from which one would hope to draw STEM and technological leadership talent. There are 1037 men and 613 women in the study.

The figures show significant gender differences in life and career preferences, which affect choices and outcomes even after ability is controlled for. (Click for larger versions.) According to the results, SMPY men are more concerned with money, prestige, success, creating or inventing something with impact, etc. SMPY women prefer time and work flexibility, want to give back to the community, and are less comfortable advocating unpopular ideas. Some of these asymmetries are at the 0.5 SD level or greater. Here are three survey items with a ~ 0.4 SD or more asymmetry:
# Society should invest in my ideas because they are more important than those of other people.

# Discomforting others does not deter me from stating the facts.

# Receiving criticism from others does not inhibit me from expressing my thoughts.
I would guess that Silicon Valley entrepreneurs and leading technologists are typically about +2 SD on each of these items! One can directly estimate M/F ratios from these parameters ...
Life Paths and Accomplishments of Mathematically Precocious Males and Females Four Decades Later  (Journal: Psychological Science)

David Lubinski, Camilla P. Benbow, and Harrison J. Kell
Vanderbilt University

Two cohorts of intellectually talented 13-year-olds were identified in the 1970s (1972–1974 and 1976–1978) as being in the top 1% of mathematical reasoning ability (1,037 males, 613 females). About four decades later, data on their careers, accomplishments, psychological well-being, families, and life preferences and priorities were collected. Their accomplishments far exceeded base-rate expectations: Across the two cohorts, 4.1% had earned tenure at a major research university, 2.3% were top executives at “name brand” or Fortune 500 companies, and 2.4% were attorneys at major firms or organizations; participants had published 85 books and 7,572 refereed articles, secured 681 patents, and amassed $358 million in grants. For both males and females, mathematical precocity early in life predicts later creative contributions and leadership in critical occupational roles. On average, males had incomes much greater than their spouses’, whereas females had incomes slightly lower than their spouses’. Salient sex differences that paralleled the differential career outcomes of the male and female participants were found in lifestyle preferences and priorities and in time allocation.
See also these poll results from the Harvard Crimson.
Crimson: ... The gender gap was also apparent in career choice. Men were far more likely to hope to eventually work in finance and entrepreneurship than women, while women were much more likely to aspire to careers in nonprofits and public service, health, and media or publishing. [ Note: these are super high achieving HARVARD kids in the survey, not state-U types ... no one has more "privilege" than they do, so I think it's fair to conclude that they might be expressing their relatively unconstrained actual preferences here. ]

The Hollow Men: video and audio

Highly recommended talk by Dominic Cummings at the UK Institute for Public Policy Research. See also The Hollow Men (original essay).

Podcast version here and below.

Thursday, November 20, 2014

Additivity and complex traits in mice

How well can we predict complex phenotypes in mice from genomic data? The figure below, from a recent Nature Genetics paper (Speed and Balding doi:10.1038/nrg3821), shows prediction accuracies for a set of 139 traits -- including behavioral and disease phenotypes. Significant chunks of heritability are easily captured by linear models with additive effects. The population of mice used in the study are derived from crosses of 8 original inbred strains (see photo). For similar predictive results in dairy cows, see here.

This suggests that human population variation in complex traits is also likely to be approximately linear: mostly due to additive genetic effects. You may have noticed that I am gradually collecting copious evidence for additivity. Far too many scientists and quasi-scientists are infected by the epistasis or epigenetics meme, which is appealing to those who "revel in complexity" and would like to believe that biology is too complex to succumb to equations. ("How can it be? But what about the marvelous incomprehensible beautiful sacred complexity of Nature? But But But ...")

I sometimes explain things this way:
There is a deep evolutionary reason behind additivity: nonlinear mechanisms are fragile and often "break" due to DNA recombination in sexual reproduction. Effects which are only controlled by a single locus are more robustly passed on to offspring. ...

Many people confuse the following statements:

"The brain is complex and nonlinear and many genes interact in its construction and operation."

"Differences in brain performance between two individuals of the same species must be due to nonlinear (non-additive) effects of genes."

The first statement is true, but the second does not appear to be true across a range of species and quantitative traits.
See also discussion in section 3 of my paper On the genetic architecture of intelligence and other complex traits.

Compare to the additive heritability estimates below. Note the different K's correspond to different choices of genetic similarity matrices (GSMs; see paper). Just ignore all the dots except the ones with largest r2 or h2 for each phenotype. All of the underlying predictive models are linear. It is possible that some phenotypes have even greater broad sense (including non-additive) heritability and that nonlinear models will be required to capture this variation.

Some examples of behavioral traits measured in this mouse population.
EPM: (maze) distance travelled, time spent, and entries into closed and open arms
FN: time taken to sample a novel foodstuff (overnight food deprivation)
Burrowing: Number of pellets removed from burrow in 1.5 hours
Activity: Activity measured in a home cage in 30 minutes
Startle: Startle to a loud noise
Context freezing: Freezing to the context in which a tone is associated with a foot shock
Cue freezing: Freezing to a tone after association with a foot shock

"We live in capitalism. Its power seems inescapable; so did the divine right of kings."

Ursula K. Le Guin, remarks at the National Book Awards. She acknowledged her fellow fantasy and sci-fi writers, who have for so long watched “the beautiful awards,” like the one she received, go to the “so-called realists.”
New Yorker: ... I think hard times are coming, when we will be wanting the voices of writers who can see alternatives to how we live now, and can see through our fear-stricken society and its obsessive technologies, to other ways of being. And even imagine some real grounds for hope. We will need writers who can remember freedom: poets, visionaries—the realists of a larger reality. Right now, I think we need writers who know the difference between production of a market commodity and the practice of an art. The profit motive is often in conflict with the aims of art. We live in capitalism. Its power seems inescapable; so did the divine right of kings. … Power can be resisted and changed by human beings; resistance and change often begin in art, and very often in our art—the art of words. I’ve had a long career and a good one, in good company, and here, at the end of it, I really don’t want to watch American literature get sold down the river. … The name of our beautiful reward is not profit. Its name is freedom.

Tuesday, November 18, 2014

20 years @15 percent: does Harvard discriminate against Asian-Americans?

This is the brief filed yesterday against Harvard, alleging discrimination against Asian-American applicants. A related suit was filed against UNC, with perhaps another to come against Wisconsin. Re: the graph above, note that Caltech has race-blind admissions.
... Harvard is engaging in racial balancing. Over an extended period, Harvard’s admission and enrollment figures for each racial category have shown almost no change. Each year, Harvard admits and enrolls essentially the same percentage of African Americans, Hispanics, whites, and Asian Americans even though the application rates and qualifications for each racial group have undergone significant changes over time. This is not the coincidental byproduct of an admissions system that treats each applicant as an individual; indeed, the statistical evidence shows that Harvard modulates its racial admissions preference whenever there is an unanticipated change in the yield rate of a particular racial group in the prior year. Harvard’s remarkably stable admissions and enrollment figures over time are the deliberate result of systemwide intentional racial discrimination designed to achieve a predetermined racial balance of its student body.
The statistical signal of managing fluctuations from year to year (evidence of a race-based target as opposed to independent individual consideration of applicants) might be even stronger for lesser Ivys, which probably see larger variations in yield compared to Harvard. It will be fascinating to see Harvard administrators and admissions officers testifying under oath as to how enrollment by ethnic group has been kept so stable over the years. Legal analysis on SCOTUSblog.

The historical parallels with anti-semitic practices of the early 20th century are reviewed in detail:
... In a letter to the chairman of the committee, President Lowell wrote that “questions of race,” though “delicate and disagreeable,” were not solved by ignoring them. The solution was a new admissions system giving the school wide discretion to limit the admission of Jewish applicants: “To prevent a dangerous increase in the proportion of Jews, I know at present only one way which is at the same time straightforward and effective, and that is a selection by a personal estimate of character on the part of the Admissions authorities ... The only way to make a selection is to limit the numbers, accepting those who appear to be the best.

... The reduction in Jewish enrollment at Harvard was immediate. The Jewish portion of Harvard’s entering class dropped from over 27 percent in 1925 to 15 percent the following year. For the next 20 years, this percentage (15 percent) remained virtually unchanged.

... The new policy permitted the rejection of scholastically brilliant students considered “undesirable,” and it granted the director of admissions broad latitude to admit those of good background with weaker academic records. The key code word used was “character” — a quality thought to be frequently lacking among Jewish applicants, but present congenitally among affluent Protestants.
This is what our country has come to:
... According to the Princeton Review: "Asian Americans comprise an increasing proportion of college students nationwide. Many Asian Americans have been extraordinarily successful academically, to the point where some colleges now worry that there are ‘too many’ Asian Americans on their campuses. Being an Asian American can now actually be a distinct disadvantage in the admissions processes at some of the most selective schools in the country ...

... If you’re given an option, don’t attach a photograph to your application and don’t answer the optional question about your ethnic background. This is especially important if you don’t have an Asian sounding surname. (By the same token, if you do have an Asian sounding surname but aren’t Asian, do attach a photograph.)"
Please do not comment on this post unless you have read the brief. Comments that are dealt with directly in the brief will be deleted. I hope at least a few serious journalists take the time to read it.

See also Defining Merit, and my Bloomberg editorial on this subject: Transparency in College Admissions.
... Schools like Harvard and Princeton brag that each year they reject numerous applicants ... who score a perfect 2400 on the SAT. How would we feel if it were revealed that almost all of these rejected top scorers, year after year, were Asian-Americans? I challenge Harvard and Princeton to refute this possibility.

Addendum: this is one of the plaintiffs, who was rejected by Harvard.
17. Applicant’s parents are first-generation immigrants to the United States from China.

18. Applicant graduated from high school ranked 1 out of 460 students by weighted and un-weighted grade point average.

19. U.S. News and World Report ranks Applicant’s high school in the top 5 percent of all high schools in the United States.

20. Applicant achieved a perfect score of 36 on the ACT. Applicant achieved a perfect score of 800 for SAT II History and a perfect score of 800 for SAT II Math. Among other academic achievements, Applicant was named an AP Scholar with distinction, a National Scholar, and a National Merit Scholarship semifinalist.

21. While in high school, Applicant participated in numerous extracurricular and volunteer activities. Among other things, Applicant was captain of the varsity tennis team, volunteered at a community tennis camp, volunteered for the high school’s student peer tutoring program, was a volunteer fundraiser for National Public Radio, and traveled to China as part of a program organized by the United States Consulate General and Chinese American Students Education and Exchange to assist students in learning English writing and presentation skills.

Thursday, November 13, 2014

de novo mutations and autism

These results suggest that autism spectrum disorder (ASD) in high functioning males may be a different condition than ASD in low-IQ males and females. They also suggest many gene targets in which small "nicks" could result in lower IQ. I believe that at least part of "normal" population variation in IQ is due to effects like these.

See also Hints of genomic dark matter. Italics in abstract below are mine.
The contribution of de novo coding mutations to autism spectrum disorder

Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.

PI Michael Wigler interview: Sequencing the genome changed everything ; Unified theory of autism.

Wednesday, November 12, 2014

National security implications of genomic technology?

Jamie Metzl on the national security implications of genomic technology.

Foreign Affairs: The Genetics Epidemic

The Revolution in DNA Science -- And What To Do About It

The revolution in genetic engineering that will make it possible for humans to actively manage our evolutionary process for the first time in our species’ history is already under way. In laboratories and clinics around the world, gene therapies are being successfully deployed to treat a range of diseases, including certain types of immune deficiency, retinal amaurosis, leukemia, myeloma, hemophilia, and Parkinson’s. This miraculous progress is only the beginning. The same already existing technologies that will soon eliminate many diseases that have victimized humans for thousands of years will almost certainly be used eventually to make our species smarter, stronger, and more robust.

The prospect of genetic engineering will be exciting to some, frightening to others, and challenging for all. If not adequately addressed, it will also likely lead to major conflict both within societies and globally. But although the science of human genetic engineering is charging forward at an exponential rate, the global policy framework for ensuring this scientific progress does not lead to destabilizing conflict barely exists at all. The time has come for a meaningful dialogue on the national security implications of the human genetic revolution that can lay the conceptual foundation for a future global policy structure seeking to prevent dangerous future conflict and abuse. ...
See also his new thriller: Genesis Code. See also Genius.

Sunday, November 09, 2014

Wandering physicists

This is funny, and does capture the tendency of physicists (not just old ones) to wander into other fields.

But the cartoon avoids the hard question (perhaps best addressed by historians of science) as to the actual value brought to other fields by physicists.

See, for example, Physicists can do stuff, Prometheus in the basement, and On Crick and Watson.
... Crick, 35, had already had a career in physics interrupted by the war and despaired of making his great contribution to science. Watson was a callow 23, fresh from Indiana.
It was clear to me that I was faced with a novelty: enormous ambition and aggressiveness, ... I am sure that, had I had more contact with, for instance, theoretical physicists, my astonishment would have been less great. In any event, there they were, speculating, pondering, angling for information. ...
Thanks for digging around down there -- what did you find, again? Great! I've got more horsepower, so I'll just connect the dots for you now... :-) From Wikipedia on Crick:
Crick had to adjust from the "elegance and deep simplicity" of physics to the "elaborate chemical mechanisms that natural selection had evolved over billions of years." He described this transition as, "almost as if one had to be born again." According to Crick, the experience of learning physics had taught him something important—hubris—and the conviction that since physics was already a success, great advances should also be possible in other sciences such as biology. Crick felt that this attitude encouraged him to be more daring than typical biologists who tended to concern themselves with the daunting problems of biology and not the past successes of physics.
Mastery of so difficult a subject granted the right to invade others.

Friday, November 07, 2014

Adaptive evolution and non-coding regions

This morning I attended an excellent talk: Adaptive Evolution of Gene Expression (see paper and video below), by Hunter Fraser of Stanford.

His results support the hypothesis that non-coding regions of the genome play at least as large a role in evolution and heritable variation as protein coding genes.

From an information-theoretic perspective, it seems obvious that there is much more information in the whole genome than in the ~20k coding regions. Without the additional information, it would not be possible to produce diverse organisms such as flies, worms, fish, and humans from very similar sets of genes/proteins. Strangely, though, I've found most biologists to be overly focused on protein sequences. Perhaps results like these will finally modify this prior.
Gene expression drives local adaptation in humans
Hunter B. Fraser
Department of Biology, Stanford University, Stanford, CA, 94305.

The molecular basis of adaptation—and in particular the relative roles of protein-coding vs. gene expression changes—has long been the subject of speculation and debate. Recently, the genotyping of diverse human populations has led to the identification of many putative “local adaptations” that differ between populations. Here I show that these local adaptations are over 10-fold more likely to affect gene expression than amino acid sequence. In addition, a novel framework for identifying polygenic local adaptations detects recent positive selection on the expression levels of genes involved in UV radiation response, immune cell proliferation, and diabetes-related pathways. These results provide the first examples of polygenic gene expression adaptation in humans, as well as the first genome-scale support for the hypothesis that changes in gene expression have driven human adaptation.

This is video of a similar talk at Berkeley.

Note Added: As I mentioned above, simple considerations suggest that the machinery of life must be much more complex than the diversity of specific proteins.
Evolution at Two Levels: On Genes and Form
Sean B Carroll

(This article is based on the Allan Wilson Memorial Lectures given at the University of California at Berkeley in October 2004.)

In their classic paper “Evolution at Two Levels in Humans and Chimpanzees,” published exactly 30 years ago, Mary-Claire King and Allan Wilson described the great similarity between many proteins of chimpanzees and humans [1]. They concluded that the small degree of molecular divergence observed could not account for the anatomical or behavioral differences between chimps and humans. Rather, they proposed that evolutionary changes in anatomy and way of life are more often based on changes in the mechanisms controlling the expression of genes than on sequence changes in proteins.

This article was a milestone in three respects. First, because it was the first comparison of a large set of proteins between closely related species, it may be considered one of the first contributions to “comparative genomics” (although no such discipline existed for another two decades). Second, because it extrapolated from molecular data to make inferences about the evolution of form, it may also be considered a pioneering study in evolutionary developmental biology. And third, its focus on the question of human evolution and human capabilities, relative to our closest living relative, marked the beginning of the quest to understand the genetic basis of the origins of human traits. Like much of Wilson and his colleagues' body of work, this contribution had a great influence on paleoanthropologists as well as molecular biologists.

The 30th anniversary of this landmark article arrives at a moment when comparative genomics, evolutionary developmental biology, and evolutionary genetics are pouring forth unprecedented amounts of new data, and the entire chimpanzee genome is available for study. It is therefore an opportune time to examine what has been and is being revealed about the relationship between evolution at the two levels of molecules and organisms, and to assess the status of King and Wilson's hypothesis concerning the predominant role of regulatory mutations in organismal evolution.

King and Wilson used the phrase “ways of life” to include both physiology and behavior (M.-C. King, personal communication) and proposed that the evolution of both anatomy and ways of life was governed by regulatory changes in the expression of genes. From the outset of this review, I make the sharp distinction between the evolution of anatomy and the evolution of physiology. Changing the size, shape, number, or color patterns of physical traits is fundamentally different from changing the chemistry of physiological processes. There is ample evidence from studies of the evolution of proteins directly involved in animal vision [2], respiration [3], digestive metabolism [4], and host defense [5] that the evolution of coding sequences plays a key role in some (but not all) important physiological differences between species. In contrast, the relative contribution of coding or regulatory sequence evolution to the evolution of anatomy stands as the more open question, and will be my primary focus.

The amount of direct evidence currently in hand is modest, and includes examples of both the evolution of coding and of non-coding, regulatory sequences contributing to morphological evolution. However, I will develop the argument, on the basis of theoretical considerations and a rapidly expanding body of empirical studies, that regulatory sequence evolution must be the major contributor to the evolution of form.

This conclusion poses particular challenges to comparative genomics. While we are often able to infer coding sequence function from primary sequences, we are generally unable to decipher functional properties from mere inspection of non-coding sequences. This has led to a bias in comparative genomics and evolutionary genetics toward the analysis and reporting of readily detectable events in coding regions, such as gene duplications and protein sequence evolution, while non-coding, regulatory sequences are often ignored. However, approximately two-thirds of all sequences under purifying selection in our genome are non-coding [6]. One consequence of the underconsideration of non-coding, regulatory sequences is unrealistic expectations about what can currently be learned about the genetic bases of morphological diversity from comparisons of genome sequences alone. The visible diversity of any group is not reflected by the most visible components of gene diversity—that is, the diversity of gene number or of coding sequences. In order to understand the evolution of anatomy, we have to study and understand regulatory sequences, as well as the proteins that connect them into the regulatory circuits that govern development. I will begin with some historical and theoretical considerations about regulatory and coding sequence evolution, then delve into the insights offered by specific experimental models of anatomical evolution, and finally, I will revisit King and Wilson's original focus and discuss how our emerging knowledge of the evolution of form bears on current efforts to understand human evolution. ...

... Thus, while the coding sequences of the structural and regulatory proteins are constrained by pleiotropy, modular cis-regulatory regions enable a great diversity of patterns to arise from alterations in regulatory circuits through the evolution of novel combinations of sites for regulatory proteins in cis-regulatory elements [35]. This diversity is produced by the sort of “tinkering” with existing components envisaged by Jacob [19]. ... The available evidence suggests ... that the diversification of other traits that are governed by highly pleiotropic and well-conserved proteins can also be accounted for by regulatory sequence evolution.

... Based upon (i) empirical studies of the evolution of traits and of gene regulation in development, (ii) the rate of gene duplication and the specific histories of important developmental gene families, (iii) the fact that regulatory proteins are the most slowly evolving of all classes of proteins, and (iv) theoretical considerations concerning the pleiotropy of mutations, I argue that there is adequate basis to conclude that the evolution of anatomy occurs primarily through changes in regulatory sequences. ...

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