Biology subjects

Alon Keinan

Publications and source records attributed to Alon Keinan.

6 recordsLinked to original sources

bioRxiv2016

High-resolution DNA accessibility profiles increase the discovery and interpretability of genetic associations

Genetic risk for common autoimmune diseases is influenced by hundreds of small effect, mostly non-coding variants, enriched in regulatory regions active in adaptive-immune cell types. DNaseI hypersensitivity sites (DHSs) are a genomic mark for regulatory DNA. Here, we generated a single DHSs annotation from fifteen deeply sequenced DNase-seq experiments in adaptive-immune as well as non-immune cell types. Using this annotation we quantified accessibility across cell types in a matrix format amenable to statistical analysis, deduced the subset of DHSs unique to adaptive-immune cell types, and grouped DHSs by cell-type accessibility profiles. Measuring enrichment with cell-type-specific TF binding sites as well as proximal gene expression and function, we show that accessibility profiles grouped DHSs into coherent regulatory functions. Using the adaptive-immune-specific DHSs as input (0.37% of genome), we associated DHSs to six autoimmune diseases with GWAS data. Associated loci showed higher replication rates when compared to loci identified by GWAS or by considering all DHSs, allowing the additional discovery of 327 loci (FDR<0.005) below typical GWAS significance threshold, 52 of which are novel and replicating discoveries. Finally, we integrated DHS associations from six autoimmune diseases, using a network model (bird-eye view) and a regulatory Manhattan plot schema (per locus). Taken together, we described and validated a strategy to leverage finely resolved regulatory priors, enhancing the discovery, interpretability, and resolution of genetic associations, and providing actionable insights for follow up work.

Genetics↗

bioRxiv2016

Positive selection on a regulatory insertion-deletion polymorphism in FADS2 influences apparent endogenous synthesis of arachidonic acid

Long chain polyunsaturated fatty acids (LCPUFA) are bioactive components of membrane phospholipids and serve as substrates for signaling molecules. LCPUFA can be obtained directly from animal foods or synthesized endogenously from 18 carbon precursors via the FADS2 coded enzyme. Vegans rely almost exclusively on endogenous synthesis to generate LCPUFA and we hypothesized that an adaptive genetic polymorphism would confer advantage. The rs66698963 polymorphism, a 22 bp insertion-deletion within FADS2, is associated with basal FADS1 expression, and coordinated induction of FADS1 and FADS2 in vitro. Here we determined rs66698963 genotype frequencies from 234 individuals of a primarily vegetarian Indian population and 311 individuals from the U.S. A much higher I/I genotype frequency was found in Indians (68%) than in the U.S. (18%). Analysis using 1000 Genomes Project data confirmed our observation, revealing a global I/I genotype of 70% in South Asians, 53% in Africans, 29% in East Asians, and 17% in Europeans. Tests based on population divergence, site frequency spectrum and long-range haplotype consistently point to positive selection encompassing rs66698963 in South Asian, African and some East Asian populations. Basal plasma phospholipid arachidonic acid status was 8% greater in I/I compared to D/D individuals. The biochemical pathway product-precursor difference, arachidonic acid minus linoleic acid, was 31% and 13% greater for I/I and I/D compared to D/D, respectively. Our study is consistent with previous in vitro data suggesting that the insertion allele enhances n-6 LCPUFA synthesis and may confer an adaptive advantage in South Asians because of the traditional plant-based diet practice.

Evolutionary Biology↗

bioRxiv2015

The genetics of Bene Israel from India reveals both substantial Jewish and Indian ancestry

The Bene Israel Jewish community from West India is a unique population whose history before the 18th century remains largely unknown. Bene Israel members consider themselves as descendants of Jews, yet the identity of Jewish ancestors and their arrival time to India are unknown, with speculations on arrival time varying between the 8th century BCE and the 6th century CE. Here, we characterize the genetic history of Bene Israel by collecting and genotyping 18 Bene Israel individuals. Combining with 486 individuals from 41 other Jewish, Indian and Pakistani populations, and additional individuals from worldwide populations, we conducted comprehensive genome-wide analyses based on FST, principal component analysis, ADMIXTURE, identity-by-descent sharing, admixture linkage disequilibrium decay, haplotype sharing and allele sharing autocorrelation decay, as well as contrasted patterns between the X chromosome and the autosomes. The genetics of Bene Israel individuals resemble local Indian populations, while at the same time constituting a clearly separated and unique population in India. They are unique among Indian and Pakistani populations we analyzed in sharing considerable genetic ancestry with other Jewish populations. Putting together the results from all analyses point to Bene Israel being an admixed population with both Jewish and Indian ancestry, with the genetic contribution of each of these ancestral populations being substantial. The admixture took place in the last millennium, about 19-33 generations ago. It involved Middle-Eastern Jews and was sex-biased, with more male Jewish and local female contribution. It was followed by a population bottleneck and high endogamy, which can lead to increased prevalence of recessive diseases in this population. This study provides an example of how genetic analysis advances our knowledge of human history in cases where other disciplines lack the relevant data to do so.

Genetics↗

bioRxiv2015

Inference of super-exponential human population growth via efficient computation of the site frequency spectrum for generalized models

The site frequency spectrum (SFS) and other genetic summary statistics are at the heart of many population genetics studies. Previous studies have shown that human populations had undergone a recent epoch of fast growth in effective population size. These studies assumed that growth is exponential, and the ensuing models leave unexplained excess amount of extremely rare variants. This suggests that human populations might have experienced a recent growth with speed faster than exponential. Recent studies have introduced a generalized growth model where the growth speed can be faster or slower than exponential. However, only simulation approaches were available for obtaining summary statistics under such models. In this study, we provide expressions to accurately and efficiently evaluate the SFS and other summary statistics under generalized models, which we further implement in a publicly available software. Investigating the power to infer deviation of growth from being exponential, we observed that decent sample sizes facilitate accurate inference, e.g. a sample of 3000 individuals with the amount of data expected from exome sequencing allows observing and accurately estimating growth with speed deviating by 10% or more from that of exponential. Applying our inference framework to data from the NHLBI Exome Sequencing Project, we found that a model with a generalized growth epoch fits the observed SFS significantly better than the equivalent model with exponential growth (p-value = 3.85 x 10-6). The estimated growth speed significantly deviates from exponential (p-value << 10-12), with the best-fit estimate being of growth speed 12% faster than exponential.

Evolutionary Biology↗

bioRxiv2014

XWAS: a software toolset for genetic data analysis and association studies of the X chromosome

XWAS is a new software suite for the analysis of the X chromosome in association studies and similar studies. The X chromosome plays an important role in human disease, especially those with sexually dimorphic characteristics. Special attention needs to be given to its analysis due to the unique inheritance pattern, which leads to analytical complications that have resulted in the majority of genome-wide association studies (GWAS) either not considering X or mishandling it with toolsets that had been designed for non-sex chromosomes. We hence developed XWAS to fill the need for tools that are specially designed for analysis of X. Following extensive, stringent, and X-specific quality control, XWAS offers an array of statistical tests of association, including: (1) the standard test between a SNP (single nucleotide polymorphism) and disease risk, including after first stratifying individuals by sex, (2) a test for a differential effect of a SNP on disease between males and females, (3) motivated by X-inactivation, a test for higher variance of a trait in heterozygous females as compared to homozygous females, and (4) for all tests, a version that allows for combining evidence from all SNPs across a gene. We applied the toolset analysis pipeline to 16 GWAS datasets of immune-related disorders and 7 risk factors of coronary artery disease, and discovered several new X-linked genetic associations. XWAS will provide the tools and incentive for others to incorporate the X chromosome into GWAS, hence enabling discoveries of novel loci implicated in many diseases and in their sexual dimorphism.

Genetics↗

bioRxiv2014

Accounting for eXentricities: Analysis of the X chromosome in GWAS reveals X-linked genes implicated in autoimmune diseases

Many complex human diseases are highly sexually dimorphic, suggesting a potential contribution of the X chromosome to disease risk. However, the X chromosome has been neglected or incorrectly analyzed in most genome-wide association studies (GWAS). We present tailored analytical methods and software that facilitate X-wide association studies (XWAS), which we further applied to reanalyze data from 16 GWAS of different autoimmune and related diseases (AID). We associated several X-linked genes with disease risk, among which (1) ARHGEF6 is associated with Crohns disease and replicated in a study of ulcerative colitis, another inflammatory bowel disease (IBD). Indeed, ARHGEF6 interacts with a gastric bacterium that has been implicated in IBD. (2) CENPI is associated with three different AID, which is compelling in light of known associations with AID of autosomal genes encoding centromere proteins, as well as established autosomal evidence of pleiotropy between autoimmune diseases. (3) We replicated a previous association of FOXP3, a transcription factor that regulates T-cell development and function, with vitiligo; and (4) we discovered that C1GALT1C1 exhibits sex-specific effect on disease risk in both IBDs. These and other X-linked genes that we associated with AID tend to be highly expressed in tissues related to immune response, participate in major immune pathways, and display differential gene expression between males and females. Combined, the results demonstrate the importance of the X chromosome in autoimmunity, reveal the potential of extensive XWAS, even based on existing data, and provide the tools and incentive to properly include the X chromosome in future studies.

Genetics↗