Tuesday, July 26, 2016

Genomics of complex traits and evolutionary selection pressure on DNA regions linked to cognitive ability

Two recent papers relevant to the genetics of complex traits. The second paper is specifically about the genetic architecture of cognition. Thanks to blog readers for pointing them out to me.

See also The tipping point.
Genetics of complex traits: prediction of phenotype, identification of causal polymorphisms and genetic architecture

DOI: 10.1098/rspb.2016.0569
Proceedings of the Royal Society 27 July 2016 Volume 283, issue 1835

Complex or quantitative traits are important in medicine, agriculture and evolution, yet, until recently, few of the polymorphisms that cause variation in these traits were known. Genome-wide association studies (GWAS), based on the ability to assay thousands of single nucleotide polymorphisms (SNPs), have revolutionized our understanding of the genetics of complex traits. We advocate the analysis of GWAS data by a statistical method that fits all SNP effects simultaneously, assuming that these effects are drawn from a prior distribution. We illustrate how this method can be used to predict future phenotypes, to map and identify the causal mutations, and to study the genetic architecture of complex traits. The genetic architecture of complex traits is even more complex than previously thought: in almost every trait studied there are thousands of polymorphisms that explain genetic variation. Methods of predicting future phenotypes, collectively known as genomic selection or genomic prediction, have been widely adopted in livestock and crop breeding, leading to increased rates of genetic improvement.

Molecular genetic aetiology of general cognitive function is enriched in evolutionarily conserved regions

http://dx.doi.org/10.1101/063636

Differences in general cognitive function have been shown to be partly heritable and to show genetic correlations with a several psychiatric and physical disease states. However, to date few single nucleotide polymorphisms (SNPs) have demonstrated genome-wide significance, hampering efforts aimed at determining which genetic variants are most important for cognitive function and which regions drive the genetic associations between cognitive function and disease states. Here, we combine multiple large genome-wide association study (GWAS) data sets, from the CHARGE cognitive consortium and UK Biobank, to partition the genome into 52 functional annotations and an additional 10 annotations describing tissue-specific histone marks. Using stratified linkage disequilibrium score regression we show that, in two measures of cognitive function, SNPs associated with cognitive function cluster in regions of the genome that are under evolutionary negative selective pressure. These conserved regions contained ~2.6% of the SNPs from each GWAS but accounted for ~ 40% of the SNP-based heritability. The results suggest that the search for causal variants associated with cognitive function, and those variants that exert a pleiotropic effect between cognitive function and health, will be facilitated by examining these enriched regions.

Monday, July 25, 2016

The Mendel of Cancer Genetics


See also earlier post Where Men are Men and Giants Walk the Earth.
NYTimes: Dr. Alfred G. Knudson, the ‘Mendel of Cancer Genetics,’ Dies at 93

Dr. Alfred G. Knudson, who deduced how certain cancers strike a family generation after generation, died on Sunday at his home in Philadelphia. He was 93.

... “Funny as it may sound, heritable cancer was hardly discussed in the 1960s and 1970s,” Dr. Albert de la Chapelle, a professor in the human genetics program at Ohio State University, said in an email.

Dr. Knudson, trained as a pediatrician, tackled the issue by looking at retinoblastoma, a cancer of the eye that strikes children, even newborns. Childhood cancers would be easier to understand, he reasoned, because there would be fewer confounding factors, like the random mutations that accumulate over a lifetime.

“It had been known for a long time that there were inherited forms of retinoblastoma, that it would run in families,” said Dr. Jonathan Chernoff, the chief scientific officer at Fox Chase. “And then there were, on the other hand, sporadic cases that didn’t run in families. Some child would randomly get retinoblastoma.”

Dr. Knudson analyzed the records of retinoblastoma patients and found that the inherited form struck children at a younger age and often in both eyes, while the sporadic cases usually involved older children and just one eye.

That led him to his “two-hit” hypothesis, and his insight that cancer sometimes results not from a particular cause, but rather from the disabling of something known today as the tumor suppressor gene.

... Dr. Chernoff said Dr. Knudson was in some ways “the Mendel of cancer genetics,” referring to Gregor Mendel, the 19th-century monk who demonstrated, through the crossbreeding of pea plants, how traits are passed from one generation to the next.

“He provided the conceptual framework for how we think about cancer now,” Dr. Chernoff said.

Dr. Knudson published his hypothesis in 1971. “Knudson’s hypothesis was conceived before we had a clue about the underlying molecular genetic events,” Dr. de la Chapelle said. “I believe Knudson’s work stimulated retinoblastoma researchers so strongly that this led to an early breakthrough.”

Dr. Knudson’s theory was proved in 1986, when researchers figured out the gene and the mutations that led to the disease.

... Alfred George Knudson Jr. was born on Aug. 9, 1922, in Los Angeles. He went to the California Institute of Technology thinking he would major in physics.

“I had never had any biology in high school,” he recalled in a 2013 interview. “Then, after two years of physics at Caltech, I thought: ‘Oh, they know everything in physics. Why do I want to go into physics?’”

The quantitative aspects of genetics appealed to him, he said: “It has some of the features I admire about physics, so I’ll study that.”

He finished his bachelor of science degree at Caltech in 1944 and went on to receive a medical degree from Columbia in 1947. He returned to Caltech to earn a doctorate in biochemistry and genetics in 1956. He served in the Navy during World War II and the Army during the Korean War.

Sunday, July 24, 2016

Scifoo 2016

Photos from Palo Alto and Scifoo 2016. We weren't allowed to take photos inside the Googleplex.










Wednesday, July 20, 2016

Farewell Asia, Hello Scifoo

Apologies for the lack of blog posts. I've been on the road in Asia and quite busy for the past week. I head back to the bay area for Scifoo this weekend. See you there!







The tipping point

This is only the beginning. To serious people who read this blog, but may have been confused over the past 5+ years about things like missing heritability, genomic prediction, complex genetic architecture, gloomy prospects: isn't it about time to consider updating your priors? Read all about it here.
FT.com: Genetic scoring predicts how children do at school

Professor Robert Plomin, senior author, called the study “a tipping point for predicting individuals’ educational strengths and weaknesses from their DNA”. It is published in the journal Molecular Psychiatry.

An individual’s “polygenic score” is based on the presence or absence of 20,000 common DNA variants across many different genes. Each has a tiny effect on its own but together they explain 10 per cent of the variation in children’s educational attainment at the age of 16.
It's important to note that 9 percent of variance accounted for implies that the resulting polygenic score predictor would correlate about 0.3 with actual educational achievement. This is similar to the correlation between high school and college grades at a typical flagship state university (note there is some restriction of range) -- not a weak predictor by the standards of social science.
Predicting educational achievement from DNA

Nature Molecular Psychiatry 19 July 2016; doi: 10.1038/mp.2016.107

A genome-wide polygenic score (GPS), derived from a 2013 genome-wide association study (N=127,000), explained 2% of the variance in total years of education (EduYears). In a follow-up study (N=329,000), a new EduYears GPS explains up to 4%. Here, we tested the association between this latest EduYears GPS and educational achievement scores at ages 7, 12 and 16 in an independent sample of 5825 UK individuals. We found that EduYears GPS explained greater amounts of variance in educational achievement over time, up to 9% at age 16, accounting for 15% of the heritable variance. This is the strongest GPS prediction to date for quantitative behavioral traits. Individuals in the highest and lowest GPS septiles differed by a whole school grade at age 16. Furthermore, EduYears GPS was associated with general cognitive ability (~3.5%) and family socioeconomic status (~7%). There was no evidence of an interaction between EduYears GPS and family socioeconomic status on educational achievement or on general cognitive ability. These results are a harbinger of future widespread use of GPS to predict genetic risk and resilience in the social and behavioral sciences.

Saturday, July 16, 2016

Monday, July 11, 2016

My neighbor's kid is a designer baby (or not)



I happened to see Knoepfler's book at the HKUST bookstore yesterday. He's a stem cell researcher at UC Davis.
GMO Sapiens: the Life-Changing Science of Designer Babies is an exciting new book which takes a look at the cutting edge biotechnology trends that are making human genetic modification and cloning a more practical potential reality in the coming years. The convergence of advances in bioengineering, genetics, genomics, assisted reproduction and stem cells have brought us to the astonishing point where literally making new forms of human beings is possible. Surprisingly, some people and organizations are strong advocates for allowing genetic modification of humans while others feel equally passionately opposed. Meanwhile, the general public is largely unaware that we have reached this remarkable turning point in human history when we can literally change what it means to be human.

As much as the public is engaged in the topic of genetically modified organism (GMO) foods, this book will capture their imaginations and fire their passions by educating them on the potential coming of GMO people while, at the same time, educating them.

Sunday, July 10, 2016

IMO at HKUST

By coincidence, they're hosting the International Math Olympiad here. There are teams of kids from all over the world, but less geeky looking than I expected.






This deck of cards was created by the HKUST math chair, formerly of MSU.

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