Thursday, January 06, 2022

BOLA2 Copy Number Variation: Phenotype Effects From A Human Accelerated Region

Human Accelerated Regions (HARs) are regions of DNA that were conserved throughout prior (e.g., vertebrate) evolution but are significantly different in the human genome.
Allen Institute: ... of the known 3,171 human accelerated regions, 99 percent of these human-specific mutations fall into "non-coding" regions of DNA, or regions of DNA that don't contain instructions for making a protein. Many of them are in stretches of our genome known as enhancers, regions which regulate nearby genes, and about half of those are nestled in enhancers that are active in the developing human brain.
Our analysis of DNA regions used in predictors for common diseases and complex human traits found that large portions of phenotype variance reside in non-coding regions. This has important consequences for pleiotropy and for our understanding of genetic architecture. 

Regarding HARs, in a 2013 post Neanderthals Dumb? I wrote:

This figure is from the Supplement (p.62) of a recent Nature paper describing a high quality genome sequence obtained from the toe of a female Neanderthal who lived in the Altai mountains in Siberia. Interestingly, copy number variation at 16p11.2 is one of the structural variants identified in a recent deCODE study as related to IQ depression; see earlier post Structural genomic variants (CNVs) affect cognition.

From the Supplement (p.62):
Of particular interest is the modern human-specific duplication on 16p11.2 which encompasses the BOLA2 gene. This locus is the breakpoint of the 16p11.2 micro-deletion, which results in developmental delay, intellectual disability, and autism5,6. We genotyped the BOLA2 gene in 675 diverse human individuals sequenced to low coverage as part of the 1000 Genome Project Phase I7 to assess the population distribution of copy numbers in homo-sapiens (Figure S8.3). While both the Altai Neandertal and Denisova individual exhibit the ancestral diploid copy number as seen in all the non-human great apes, only a single human individual exhibits this diploid copy number state.

Modern humans typically have many (e.g., 3-10) copies of BOLA2. In Neanderthals and apes, 2 copies. 
Variation in copy number presumably affects gene expression, even if the actual protein (coding base pairs) structure is not changed. There may be other mechanisms at work, of course.

Mutations in this 16p11.2 region are associated with schizophrenia, autism, brain size, reduced IQ, anemia, and other things. 

Since 2013 a number of papers have investigated the phenotype effects of BOLA2 copy number variation (CNV) and/or the 16p11.2 duplication/deletion. The latter is more complex as it affects multiple genes in addition to BOLA2. In the future, using whole exome or whole genome data in UKB, it should be possible to focus more specifically on effects of BOLA2 CNV.

For reference I note some of the results below.
Phenome-wide Burden of Copy-Number Variation in the UK Biobank (2019) 
16p11.2 C deletion: "We observe significant increases, on the order of one standard deviation, in weight, BMI, hip and waist circumference, reticulocyte count, and Cystatin C measures for these individuals. The larger 593 kb CNV associates with similar measures of body size and fat, as well as hypertension, diabetes/HbA1c, and abdominal hernia. These results are also indicative of effects due to developmental delay; namely, decreased measures of memory, higher Townsend deprivation (an index of material deprivation which considers employment, home/auto ownership, and household overcrowding in a person's neighborhood) ..."   
Note the effect sizes, e.g., on Townsend deprivation index, are extremely large, roughly 1 SD. The effect size for Prospective Memory score (related to ability to read, remember, and execute directions) is 2 SD!



Medical consequences of pathogenic CNVs in adults: analysis of the UK Biobank (2019)
Population percentage in parenthesis: 

See also:

The Human-Specific BOLA2 Duplication Modifies Iron Homeostasis and Anemia Predisposition in Chromosome 16p11.2 Autism Individuals (2019)
Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study (2018)

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