On the Distribution of Tract Lengths During Adaptive Introgression

Admixture is increasingly being recognized as an important factor in evolutionary genetics. The distribution of genomic admixture tracts, and the resulting effects on admixture linkage disequilibrium, can be used to date the timing of admixture between species or populations. However, the theory used for such prediction assumes selective neutrality despite the fact that many famous examples of admixture involve natural selection acting for or against admixture. In this paper, we investigate the effects of positive selection on the distribution of tract lengths. We develop a theoretical framework that relies on approximating the trajectory of the selected allele using a logistic function. By numerically calculating the expected allele trajectory, we also show that the approach can be extended to cases where the logistic approximation is poor due to the effects of genetic drift. Using simulations, we show that the model is highly accurate under most scenarios. We use the model to show that positive selection on average will tend to increase the admixture tract length. However, perhaps counter-intuitively, conditional on the allele frequency at the time of sampling, positive selection will actually produce shorter expected tract lengths. We discuss the consequences of our results in interpreting the timing of the introgression of EPAS1 from Denisovans into the ancestors of Tibetans.

On the distribution of tract lengths during adaptive introgression

ABSTRACTAdmixture is increasingly being recognized as an important factor in evolutionary genetics. The distribution of genomic admixture tracts, and the resulting effects on admixture linkage disequilibrium, can be used to date the timing of admixture between species or populations. However, the theory used for such prediction assumes selective neutrality despite the fact that many famous examples of admixture involve natural selection acting for or against admixture. In this paper, we investigate the effects of positive selection on the distribution of tract lengths. We develop a theoretical framework that relies on approximating the trajectory of the selected allele using a logistic function. By numerically calculating the expected allele trajectory, we also show that the approach can be extended to cases where the logistic approximation is poor due to the effects of genetic drift. Using simulations, we show that the model is highly accurate under most scenarios. We use the model to show that positive selection on average will tend to increase the admixture tract length. However, perhaps counter-intuitively, conditional on the allele frequency at the time of sampling, positive selection will actually produce shorter expected tract lengths. We discuss the consequences of our results in interpreting the timing of the introgression of EPAS1 from Denisovans into the ancestors of Tibetans.

Resolution of conflict between parental genomes in a hybrid species

The development of reproductive barriers against parent species is crucial during hybrid speciation, and post-zygotic isolation can be important in this process. Genetic incompatibilities that normally isolate the parent species can become sorted in hybrids to form reproductive barriers towards either parent. However, the extent to which this sorting process is systematically biased and therefore predictable in which loci are involved and which alleles are favored is largely unknown. Theoretically, reduced fitness in hybrids due to the mixing of differentiated genomes can be resolved through rapid evolution towards allelic combinations ancestral to lineage-splitting of the parent species, as these alleles have successfully coexisted in the past. However, for each locus, this effect may be influenced by its chromosomal location, function, and interactions with other loci. We use the Italian sparrow, a homoploid hybrid species that has developed post-zygotic barriers against its parent species, to investigate this prediction. We show significant bias towards fixation of the ancestral allele among 57 nuclear intragenic SNPs, particularly those with a mitochondrial function whose ancestral allele came from the same parent species as the mitochondria. Consistent with increased pleiotropy leading to stronger fitness effects, genes with more protein-protein interactions were more biased in favor of the ancestral allele. Furthermore, the number of protein-protein interactions was especially low among candidate incompatibilities still segregating within Italian sparrows, suggesting that low pleiotropy allows steep intraspecific clines in allele frequencies to form. Finally, we report evidence for pervasive epistatic interactions within one Italian sparrow population, particularly involving loci isolating the two parent species but not hybrid and parent. However there was a lack of classic incompatibilities and no admixture linkage disequilibrium. This suggests that parental genome admixture can continue to constrain evolution and prevent genome stabilization long after incompatibilities have been purged.

Inference of multiple-wave population admixture by modeling decay of linkage disequilibrium with polynomial functions

To infer the histories of population admixture, one important challenge with methods based on the admixture linkage disequilibrium (ALD) is to get rid of the effect of source LD (SLD) which is directly inherited from source populations. In previous methods, only the decay curve of weighted LD between pairs of sites whose genetic distance were larger than a certain starting distance was fitted by single or multiple exponential functions, for the inference of recent single- or multiple-wave of admixture. However, the effect of SLD has not been well defined and no tool has been developed to estimate the effect of SLD on weighted LD decay. In this study, we defined the SLD in the formularized weighted LD statistic under the two-way admixture model, and proposed polynomial spectrum (p-spectrum) to study the weighted SLD and weighted LD. We also found reference populations could be used to reduce the SLD in weighted LD statistic. We further developed a method, iMAAPs, to infer Multiple-wave Admixture by fitting ALD using Polynomial spectrum. We evaluated the performance of iMAAPs under various admixture models in simulated data and applied iMAAPs into analysis of genome-wide single nucleotide polymorphism data from the Human Genome Diversity Project (HGDP) and the HapMap Project. We showed that iMAAPs is a considerable improvement over other current methods and further facilitates the inference of the histories of complex population admixtures.

Estimating the timing of multiple admixture events using 3-locus Linkage Disequilibrium

Estimating admixture histories is crucial for understanding the genetic diversity we see in present-day populations. Existing allele frequency or phylogeny-based methods are excellent for inferring the existence of admixture or its proportions, but have less power for estimating admixture times. Recently introduced approaches for estimating these times use spatial information from admixed chromosomes, such as the local ancestry or the decay of admixture linkage disequilibrium (ALD). One popular method, implemented in the programs ALDER and ROLLOFF, uses two-locus ALD to infer the time of a single admixture event, but is only able to estimate the time of the most recent admixture event based on this summary statistic. We derive analytical expressions for the expected ALD in a three-locus system and provide a new statistical method based on these results that is able to resolve more complicated admixture histories. Using simulations, we show how this new statistic behaves on a range of admixture histories. As an example, we also apply our method to the Colombian and Mexican samples from the 1000 Genomes project.

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.

Regions on Chromosomes 1 and 14 Are Associated with VWF:Ag Levels in African Americans Using Mapping By Admixture Linkage Disequilibrium

Background: VWF:Ag is highly heritable, however, despite genome-wide linkage and association analysis, mostly in European derived populations, the genetic basis for VWF levels is only partially understood. African Americans (AfAm) have significantly higher VWF:Ag than European Americans: although variants in VWF and ABO can account for some of this, it is not clear whether they explain all of this ethnic difference. A powerful method to identify chromosomal regions that account for ethnic differences is mapping by admixture linkage disequilibrium (MALD). MALD uses markers that differ markedly in allele frequency between ancestral populations, estimates the global ancestry for each individual, and compares local ancestry between subjects with different trait values to global estimates to identify regions of the genome that account for the ethnic differences of a trait. Hypothesis: Loci that are associated with VWF:Ag levels in AfAm can be mapped using MALD. Methods: From 188 AfAm healthy volunteers from the Zimmerman Program for the Molecular and Clinical Biology of VWD, 96 were selected to have 98≤VWF:Ag≥ 164 IU which represent the <25% and >75% of VWF:Ag distribution. They were genotyped using Illumina HumanCoreExome genome-wide SNP chip. SNPs were selected for MALD if they had allele frequency difference between ancestral population (YRI and CEU from HapMap) of >0.4. Related and non-admixed individuals were excluded. Extreme trait analysis was performed using ADMIXMAP. Results: 16 males and 68 females (mean age 41 years, SD=13) of whom 41 had with Ag≤98and 43 with Ag ≥164 IU were subjected to analysis with 2254 ancestry informative markers across the genome with a mean spacing of 1.8 cM (1.3 Mb). Estimated African ancestry was 79% (SD=13%, range 24-96%), while European ancestry was 20% (SD=12%, range 4-72%). Comparing the subjects at extremes of VWF, regions on chrs 1 (110-147 Mb) and 14 (22-40 Mb) had |Z| scores >3 (p<0.0025) which is the conventional cut-off in MALD studies. At chrs 1 and 14, greater African admixture was associated with higher VWF:Ag, consistent with the expected direction. No significant admixture signal was observed at the VWF (p=0.39) or ABO (p=0.48) loci, which may represent low power due to small sample size. Discussion: These pilot results require replication in a larger number of independent subjects, as well as fine-mapping to identify the underlying variants responsible for differences in VWF between individuals. Disclosures No relevant conflicts of interest to declare.