AdmixSim 2: a forward-time simulator for modeling complex population admixture

Background Computer simulations have been widely applied in population genetics and evolutionary studies. A great deal of effort has been made over the past two decades in developing simulation tools. However, there are not many simulation tools suitable for studying population admixture. Results We here developed a forward-time simulator, AdmixSim 2, an individual-based tool that can flexibly and efficiently simulate population genomics data under complex evolutionary scenarios. Unlike its previous version, AdmixSim 2 is based on the extended Wright-Fisher model, and it implements many common evolutionary parameters to involve gene flow, natural selection, recombination, and mutation, which allow users to freely design and simulate any complex scenario involving population admixture. AdmixSim 2 can be used to simulate data of dioecious or monoecious populations, autosomes, or sex chromosomes. To our best knowledge, there are no similar tools available for the purpose of simulation of complex population admixture. Using empirical or previously simulated genomic data as input, AdmixSim 2 provides phased haplotype data for the convenience of further admixture-related analyses such as local ancestry inference, association studies, and other applications. We here evaluate the performance of AdmixSim 2 based on simulated data and validated functions via comparative analysis of simulated data and empirical data of African American, Mexican, and Uyghur populations. Conclusions AdmixSim 2 is a flexible simulation tool expected to facilitate the study of complex population admixture in various situations.

Evaluating the Impact of Sex-Biased Genetic Admixture in the Americas through the Analysis of Haplotype Data

A general imbalance in the proportion of disembarked males and females in the Americas has been documented during the Trans-Atlantic Slave Trade and the Colonial Era and, although less prominent, more recently. This imbalance may have left a signature on the genomes of modern-day populations characterised by high levels of admixture. The analysis of the uniparental systems and the evaluation of continental proportion ratio of autosomal and X chromosomes revealed a general sex imbalance towards males for European and females for African and Indigenous American ancestries. However, the consistency and degree of this imbalance are variable, suggesting that other factors, such as cultural and social practices, may have played a role in shaping it. Moreover, very few investigations have evaluated the sex imbalance using haplotype data, containing more critical information than genotypes. Here, we analysed genome-wide data for more than 5000 admixed American individuals to assess the presence, direction and magnitude of sex-biased admixture in the Americas. For this purpose, we applied two haplotype-based approaches, ELAI and NNLS, and we compared them with a genotype-based method, ADMIXTURE. In doing so, besides a general agreement between methods, we unravelled that the post-colonial admixture dynamics show higher complexity than previously described.

Forensic characteristics and population construction of two major minorities from southwest China revealed by a novel 37 Y-STR loci system

Y-chromosome short tandem repeats (Y-STRs) have become important supplementary evidence in forensic science. Nowadays, the Y-chromosome STR haplotype reference database (YHRD) contains abundant Y-STR haplotype data from all over the world, while haplotype data of Guizhou Miao and Tujia are scarce. Hence, genetic polymorphisms of 37 Y-STRs were investigated in 446 unrelated males (206 Miao males and 246 Tujia males) residing in Guizhou Province. A total of 206 and 242 unique haplotypes with the highest diversity value of 0.9665 and 0.9470 were obtained. The heatmap, multidimensional scaling (MDS), the unweighted pair-group method with arithmetic means (UPGMA) tree and principal component analysis (PCA) based on the genetic distance (Rst) value within our studied populations and other 26 populations indicated that population structures follow the boundary of the continent. Guizhou Miao and Guizhou Tujia populations have intimate relationships with East Asian populations, especially the geographically close, similar history and the same language family populations.

Properties of Two-Locus Genealogies and Linkage Disequilibrium in Temporally Structured Samples

Archaeogenetics has been revolutionary, revealing insights into demographic history and recent positive selection in many organisms. However, most studies to date have ignored the non-random association of genetic variants at different loci (i.e., linkage disequilibrium, LD). This may be in part because basic properties of LD in samples from different times are still not well understood. Here, we derive several results for summary statistics of haplotypic variation under a model with time-stratified sampling: 1) The correlation between the number of pairwise differences observed between time-staggered samples (ΠΔt) in models with and without strict population continuity; 2) The product of the LD coeficient, D, between ancient and modern samples, which is a measure of haplotypic similarity between modern and ancient samples; and 3) The expected switch rate in the Li and Stephens haplotype copying model. The latter has implications for genotype imputation and phasing in ancient samples with modern reference panels. Overall, these results provide a characterization of how haplotype patterns are affected by sample age, recombination rates, and population sizes. We expect these results will help guide the interpretation and analysis of haplotype data from ancient and modern samples.

Historical trends and new surveillance of Plasmodium falciparum drug resistance markers in Angola

Background Plasmodium falciparum resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) has historically posed a major threat to malaria control throughout the world. The country of Angola officially replaced CQ with artemisinin-based combination therapy (ACT) as a first-line treatment in 2006, but malaria cases and deaths have recently been rising. Many classic resistance mutations are relevant for the efficacy of currently available drugs, making it important to continue monitoring their frequency in Angola. Methods Plasmodium falciparum DNA was sampled from the blood of 50 hospital patients in Cabinda, Angola from October-December of 2018. Each infection was genotyped for 13 alleles in the genes crt, mdr1, dhps, dhfr, and kelch13, which are collectively involved in resistance to six common anti-malarials. To compare frequency patterns over time, P. falciparum genotype data were also collated from studies published from across Angola in the last two decades. Results The two most important alleles for CQ resistance, crt 76T and mdr1 86Y, were found at respective frequencies of 71.4% and 6.5%. Historical data suggest that mdr1 N86 has been steadily replacing 86Y throughout Angola in the last decade, while the frequency of crt 76T has been more variable across studies. Over a third of new samples from Cabinda were ‘quintuple mutants’ for SP resistance in dhfr/dhps, with a sixth mutation at dhps A581G present at 9.6% frequency. The markers dhfr 51I, dhfr 108N, and dhps 437G have been nearly fixed in Angola since the early 2000s, whereas dhfr 59R may have risen to high frequency more recently. Finally, no non-synonymous polymorphisms were detected in kelch13, which is involved in artemisinin resistance in Southeast Asia. Conclusions Genetic markers of P. falciparum resistance to CQ are likely declining in frequency in Angola, consistent with the official discontinuation of CQ in 2006. The high frequency of multiple genetic markers of SP resistance is consistent with the continued public and private use of SP. In the future, more complete haplotype data from mdr1, dhfr, and dhps will be critical for understanding the changing efficacy of multiple anti-malarial drugs. These data can be used to support effective drug policy decisions in Angola.

Haplotype data and forensic evaluation of 23 Y-STR and 12 X-STR loci in eight ethnic groups from Eritrea

Eritrea is a multi-ethnic country of over 3 million of people consisting of different ethnic groups, having each its own language and cultural tradition. Due to the lack of population genetic data for markers of forensic interest, in this study, we analyzed the genetic polymorphisms of 23 Y-chromosome STR loci and of 12 X-chromosome STR loci in a sample of 255 unrelated individuals from 8 Eritrean ethnic groups, with the aim to generate a reference haplotype database for anthropological and forensic applications. X- and Y-chromosomes markers may indeed offer information especially in personal identification and kinship testing, when relying on the availability of large local population data to derive sufficiently accurate frequency estimates. The population genetic analyses in the Eritrean sample for both the two set of Y- and X-STR markers showed high power of discrimination both at country-based and population levels. Comparison population results highlight the importance of considering the ethnic composition within the analyzed country and the necessity of increasing available data especially when referring to heterogeneous populations such as the African ones.

Inference of Chromosome-Length Haplotypes Using Genomic Data of Three or a Few More Single Gametes

Compared with genomic data of individual markers, haplotype data provide higher resolution for DNA variants, advancing our knowledge in genetics and evolution. Although many computational and experimental phasing methods have been developed for analyzing diploid genomes, it remains challenging to reconstruct chromosome-scale haplotypes at low cost, which constrains the utility of this valuable genetic resource. Gamete cells, the natural packaging of haploid complements, are ideal materials for phasing entire chromosomes because the majority of the haplotypic allele combinations has been preserved. Therefore, compared with the current diploid-based phasing methods, using haploid genomic data of single gametes may substantially reduce the complexity in inferring the donor’s chromosomal haplotypes. In this study, we developed the first easy-to-use R package, Hapi, for inferring chromosome-length haplotypes of individual diploid genomes with only a few gametes. Hapi outperformed other phasing methods when analyzing both simulated and real single gamete cell sequencing data sets. The results also suggested that chromosome-scale haplotypes may be inferred by using as few as three gametes, which has pushed the boundary to its possible limit. The single gamete cell sequencing technology allied with the cost-effective Hapi method will make large-scale haplotype-based genetic studies feasible and affordable, promoting the use of haplotype data in a wide range of research.

A Likelihood Approach for Uncovering Selective Sweep Signatures from Haplotype Data

Selective sweeps are frequent and varied signatures in the genomes of natural populations, and detecting them is consequently important in understanding mechanisms of adaptation by natural selection. Following a selective sweep, haplotypic diversity surrounding the site under selection decreases, and this deviation from the background pattern of variation can be applied to identify sweeps. Multiple methods exist to locate selective sweeps in the genome from haplotype data, but none leverages the power of a model-based approach to make their inference. Here, we propose a likelihood ratio test statistic T to probe whole-genome polymorphism data sets for selective sweep signatures. Our framework uses a simple but powerful model of haplotype frequency spectrum distortion to find sweeps and additionally make an inference on the number of presently sweeping haplotypes in a population. We found that the T statistic is suitable for detecting both hard and soft sweeps across a variety of demographic models, selection strengths, and ages of the beneficial allele. Accordingly, we applied the T statistic to variant calls from European and sub-Saharan African human populations, yielding primarily literature-supported candidates, including LCT, RSPH3, and ZNF211 in CEU, SYT1, RGS18, and NNT in YRI, and HLA genes in both populations. We also searched for sweep signatures in Drosophila melanogaster, finding expected candidates at Ace, Uhg1, and Pimet. Finally, we provide open-source software to compute the T statistic and the inferred number of presently sweeping haplotypes from whole-genome data.

Focusing on human haplotype diversity in numerous individual genomes demonstrates an evolutional feature of each locus

The application of current genome-wide sequencing techniques on human populations helps elucidate the considerable gene flow among genus Homo, which includes modern and archaic humans. Gene flow among current human populations has been studied using frequencies of single nucleotide polymorphisms. Unlike single nucleotide polymorphism frequency data, haplotype data are suitable for identifying and tracing rare evolutionary events. Haplotype data can also conveniently detect genomic location and estimate molecular function that may be a target of selection. We analyzed eight loci of the human genome using the same procedure for each locus to infer human haplotype diversity and reevaluate past explanations of the evolutionary mechanisms that affected these loci. These loci have been recognized by separate studies because of their unusual gene genealogy and geographic distributions that are inconsistent with the recent out-of-Africa model. For each locus, we constructed genealogies for haplotypes using sequence data of the 1000 Genomes Project. Then, we performed S* analysis to estimate distinct gene flow events other than out-of-Africa events. Furthermore, we also estimated unevenness of selective pressure between haplotypes by Extended Haplotype Homozygosity analysis. Based on the patterns of results obtained by this combination of analyses, we classified the examined loci without using a specific population model. This simple method helped clarify evolutionary events for each locus, including rare evolutionary events such as introgression, incomplete lineage sorting, selection, and haplotype recombination that may be hard to discriminate from each other.

Haplotype Analysis of GJB2 Mutations: Founder Effect or Mutational Hot Spot?

The GJB2 gene is the most frequent cause of congenital or early onset hearing loss worldwide. In this study, we investigated the haplotypes of six GJB2 mutations frequently observed in Japanese hearing loss patients (i.e., c.235delC, p.V37I, p.[G45E; Y136X], p.R143W, c.176_191del, and c.299_300delAT) and analyzed whether the recurring mechanisms for each mutation are due to founder effects or mutational hot spots. Furthermore, regarding the mutations considered to be caused by founder effects, we also calculated the age at which each mutation occurred using the principle of genetic clock analysis. As a result, all six mutations were observed in a specific haplotype and were estimated to derive from founder effects. Our haplotype data together with their distribution patterns indicated that p.R143W and p.V37I may have occurred as multiple events, and suggested that both a founder effect and hot spot may be involved in some mutations. With regard to the founders’ age of frequent GJB2 mutations, each mutation may have occurred at a different time, with the oldest, p.V37I, considered to have occurred around 14,500 years ago, and the most recent, c.176_191del, considered to have occurred around 4000 years ago.