The Keinan lab aims to improve the search for complex disease genes and genes underlying other complex traits, with the key driving hypothesis being that characterizing human population genomics can inform the design and analysis of medical genetic studies. This hypothesis received fresh support from the lab's work on the effect that recent human explosive population growth has had on the accumulation of rare genetic variants and the extensive implications of that discovery for gene-disease association studies (Keinan & Clark, Science 2012). Hence, the lab studies how demographic history and natural selection have shaped patterns of human genetic variation, and translates that knowledge to the study of the genetic basis of complex human diseases. Members of the lab come from varied backgrounds, including in computer science, statistics, genetics, genomics, physics, anthropology, and biology, which enables the collaborative development of computational and statistical methods, their efficient application to large-scale, genomic data sets, and the interpretation of discoveries in light of gene function and anthropological evidence.
The X-Factor of Complex Disease
Methods, software, and extensive application for studying the X chromosome in association studies
- XWAS: a toolset for genetic data analysis and association studies of the X chromosome. Journal of Heredity. Gao F, Chang D, Biddanda A, Ma L, Guo Y, Zhou Z, Keinan A. Advance Online Pub. (2015)
- Accounting for eXentricities: Analysis of the X Chromosome in GWAS Reveals X-Linked Genes Implicated in Autoimmune Diseases. PloS one. Chang D, Gao F, Slavney A, Ma L, Waldman YY, Sams AJ, Billing-Ross P, Madar A, Spritz R, Keinan A. 9(12):e113684 (2014)
- X-inactivation informs variance-based testing for X-linked association of a quantitative trait. BMC Genomics. Ma L, Hoffman G, Keinan A. 16:241 (2015)
- Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals. Proceedings of the National Academy of Sciences of the United States of America. Ye K, Lu J, Ma F, Keinan A, Gu Z. (2014)
Recent human population growth
- Recent explosive human population growth has resulted in an excess of rare genetic variants. Science. Keinan A, Clark AG. 336:740–743 (2012)
- Neutral genomic regions refine models of recent rapid human population growth. Proceedings of the National Academy of Sciences of the United States of America. Gazave E, Ma L, Chang D, Coventry A, Gao F, Muzny D, Boerwinkle E, Gibbs RA, Sing CF, Clark AG et al. 111(2):757-62 (2014)
- High burden of private mutations due to explosive human population growth and purifying selection. BMC Genomics. Gao F, Keinan A. 15(Suppl 4)(S3) (2014)
- Inference of Super-exponential Human Population Growth via Efficient Computation of the Site Frequency Spectrum for Generalized Models. Genetics. Gao F, Keinan A.
Contrasting patterns of genetic variation between chromosome X and autosomes
The genetic diversity of chromosome X is expected, under equilibrium conditions, to be three-quarters of that of the autosomes in a population with equal numbers of males and females. However, deviations from this ratio can result from at least four factors known to have been prevalent in human history: (i) sex-biased demographic events leading to different effective population sizes of males and females; (ii) changes in population size over time; (iii) natural selection, which also affects chromosome X differently; and (iv) differences in mutation rates between sexes or between chromosome X and the autosomes. We are interested in understanding how these factors have shaped the varying patterns of variation of X and A in different human populations.
Some related publications:
- Accelerated genetic drift on chromosome X during the human dispersal out of Africa. Nat. Genet. Keinan A, Mullikin JC, Patterson N, Reich D. 41:66–70 (2009)
- Analyses of X-linked and autosomal genetic variation in population-scale whole genome sequencing. Nat. Genet. Gottipati S, Arbiza L, Siepel A, Clark AG, Keinan A. 43:741–743 (2011)
- Contrasting X-linked and autosomal diversity across 14 human populations. American journal of human genetics. Arbiza L, Gottipati S, Siepel A, Keinan A. 94(6):827-44 (2014)
- NRE: a tool for exploring neutral loci in the human genome. BMC Bioinformatics. Arbiza L, Zhong E, Keinan A. 13(1):301 (2012)
Strong Constraint on Human Genes Escaping X-Inactivation Is Modulated by their Expression Level and Breadth in Both Sexes. Molecular Biology and Evolution. Slavney A, Arbiza L, Clark AG, Keinan A. 33(2):384-393 (2015)
- Indigenous Arabs are descendants of the earliest split from ancient Eurasian populations.. Genome research. Rodriguez-Flores JL, Fakhro K, Agosto-Perez F, Ramstetter MD, Arbiza L, Vincent TL, Robay A, Malek JA, Suhre K, Chouchane L et al.. 26(2):151-62 (2016)
The genetic basis of complex human disease and other complex traits
Genome-wide association studies (GWAS) have provided important insights into the genetic basis of complex human diseases and traits. At the same time, the current generation of GWAS has left us with the challenge of "missing heritability," whereby for most complex diseases and traits only a relatively small fraction of estimated heritability has been explained to day. We develop and apply statistical and computational methods for detecting the contribution of gene-gene interactions (epistasis), rare genetic variants, and the sex chromosomes to complex disease risk, thereby elucidating the role they play in explaining missing heritability. This work is in collaboration with several GWAS consortia. Further, we make the software that implements our methods publicly available, which allows application in additional studies, thereby accelerating the understanding of complex disease etiology. Our main foci are autoimmune diseases and lipid levels as risk factors of coronary artery disease.
Some related publications:
- Principal component analysis characterizes shared pathogenetics from genome-wide association studies.. PLoS computational biology. Chang D, Keinan A. 10(9):e1003820 (2014)
- Gene-based testing of interactions in association studies of quantitative traits. PLoS Genet. Ma L, Clark AG, Keinan A. 9:e1003321 (2013)
- Knowledge-driven analysis identifies a gene-gene interaction affecting high-density lipoprotein cholesterol levels in multi-ethnic populations. PLoS Genet. Ma L, Brautbar A, Boerwinkle E, Sing CF, Clark AG, Keinan A. 8:e1002714 (2012)
- Predicting signatures of "synthetic associations" and "natural associations" from empirical patterns of human genetic variation. PLoS Comput. Biol. Chang D, Keinan A. 8:e1002600 (2012)
- Interaction between SNPs in the RXRA and near ANGPTL3 gene region inhibits apoB reduction after statin-fenofibric acid therapy in individuals with mixed dyslipidemia. J. Lipid Res. Ma L, Ballantyne CM, Belmont JW, Keinan A, Brautbar A. 53:2425–2428 (2012)
Biological Knowledge-Driven Analysis of Epistasis in Human GWAS with Application to Lipid Traits. Epistasis. Ma L, Keinan A, Clark AG. 1253:35-45 (2015)