Biology subjects

Moorjani, P.

Publications and source records attributed to Moorjani, P..

17 recordsLinked to original sources

bioRxiv2026

Long-term small effective population size, inbreeding, and a recessive lethal haplotype drive premature death in the endangered Devils Hole pupfish (Cyprinodon diabolis)

As anthropogenic habitat fragmentation and population decline accelerate globally, growing numbers of species face compounding demographic and genetic threats to long-term survival. Many populations are already forced to persist at chronically small sizes, yet the genomic and fitness consequences of this fate remain poorly understood. Here we leverage the demographic history of the Devils Hole pupfish to investigate how long-term small population size and recent bottlenecks have shaped genetic diversity, genetic load, inbreeding, and fitness through comparative population genomics, historical sequencing, and sampling embryos that died prematurely during development. We find that genetic diversity in Devils Hole pupfish is among the lowest recorded in the wild and that fixed load is high, consistent with thousands of generations of isolation at small population size. Even in the face of this low diversity and high fixed load, we show that inbreeding is still strongly associated with premature embryonic death, which affects up to 25% of offspring in the captive refuge and can be identified in advance based on a characteristic elongated heart tube and reduced heart rate. We discovered a recessive lethal haplotype segregating at [~]20% frequency that accounts for 50% of embryonic deaths and contains mutations in MIB1 and MMP16, genes associated with cardiomyopathy and atrial fibrillation. Our findings link genotype, phenotype, and fitness in an iconic endangered species to provide a rare comprehensive view into the evolutionary dynamics and consequences of long-term small effective population size, demonstrating that endangered species remain vulnerable to inbreeding depression despite extremely low genetic diversity.

evolutionary biology↗

bioRxiv2026

Recovering signatures of archaic introgression using ancestral recombination graphs

Neanderthal and Denisovan genomes have reshaped our understanding of archaic introgression. Yet, the limited number of archaic genomes sequenced and the reliance on unadmixed outgroups have left much of this history unresolved. We introduce TRACE, a method to identify archaic ancestry using features of ancestral recombination graphs inferred from contemporary genomes alone. Simulations show that TRACE reliably detects archaic introgression without requiring archaic genomes or unadmixed outgroups. Applied to 1000 Genomes data, TRACE recovers known Neanderthal and Denisovan introgression and reveals signals of ghost admixture from previously uncharacterized hominins in both Africans and non-Africans. Strikingly, ghost ancestry persists in Neanderthal and Denisovan ancestry deserts, challenging their interpretation as Homo sapiens-specific regions. In Oceanians, TRACE finds deep lineages enriched in Denisovan--and not Neanderthal--regions, supporting a model of super-archaic gene flow. TRACE provides a scalable framework for mapping the legacy of archaic introgression in the absence of archaic genome sequences.

evolutionary biology↗

bioRxiv2026

Evaluating the applicability of kinship analyses for sedimentary ancient DNA datasets

Kinship reconstruction in ancient populations provides key insights into past social organization and evolutionary history. Sedimentary ancient DNA (sedaDNA) enables access to deep-time human populations in the absence of skeletal remains. However, it is characterized by severe degradation and the potential mixture of genetic material from multiple individuals, raising questions about its suitability for kinship inference. Here, we use extensive simulations to evaluate the feasibility and limitations of kinship inference in sparse and damaged sedaDNA data, with a focus on Neandertals. We find that the main obstacle to accurate kinship inference in sedaDNA is the presence of multiple contributors to a given sample. To address this, we introduce a simple heterozygosity-based test to identify samples containing DNA from multiple individuals. Guided by these results, we analyze published Neandertal sedaDNA from the Galeria de las Estatuas site to assess the practical limits of kinship inference in real sedimentary ancient DNA data. Together, our results define methodological considerations and practical limits for kinship inference in sedimentary ancient DNA.

bioinformatics↗

bioRxiv2026

Estimate of the mutation rate in the endangered Devils Hole pupfish provides support for the drift-barrier hypothesis at an outlying extreme

Mutation rates vary by orders of magnitude across eukaryotes. The drift-barrier hypothesis proposes that drift overwhelms selection for lower mutation rates in small populations, leading to higher mutation rates over time due to the gradual accumulation of mutator alleles. Here, we test this hypothesis in one of the smallest long-term isolated populations in the world, the endangered Devils Hole pupfish (Cyprinodon diabolis). We estimated germline mutation rates in adults and embryos that died prematurely using autozygous segments due to recent inbreeding events. Our estimate of 8.09 x 10-9 per base pair per generation was higher than the mean rate for actinopterygian fishes of 5.97 x 10-9 (95% CI: 4.39 x 10-9 - 7.55 x 10-9) but was lower than predicted for such a low effective population size based on a recent meta-analysis of vertebrate mutation rates and similar to species with much larger effective population sizes, contradicting the drift barrier hypothesis. We also found that embryos which died during development had a higher mutation rate than mature adults, potentially reflecting a segregating lethal mutator allele. We analyzed the mutational spectra of germline mutations and found that spectra between embryonic lethal and mature adults were similar and comparable to other fishes, despite environmental differences in temperature, oxygen saturation, and UV exposure. Mutation rates in this endangered species provide new insights into the mechanisms driving mutation rate variation across vertebrates at one extreme of low effective population size in nature.

evolutionary biology↗

bioRxiv2025

Revisiting the Evolution of Lactase Persistence: Insights from South Asian Genomes

Lactase persistence (LP), the ability to digest lactose from milk into adulthood, is a classic example of natural selection in humans. Multiple mutations upstream of the LCT gene are associated with LP and have been previously shown to be under selection in Europeans and Africans. South Asia is the worlds largest producer of dairy, and milk and dairy products are widely consumed throughout the subcontinent. However, the origin, evolutionary history and selective pressures associated with LP in South Asia remain elusive. We assembled genome-wide data from [~]8,000 present-day and ancient genomes from India, Pakistan, and Bangladesh, spanning diverse timescales ([~]3300 BCE-1650 CE), geographic regions, and ethnolinguistic and subsistence groups. We find that the Eurasian LP-associated variant,-13.910:C>T, is widespread across South Asia, exhibiting clinal variation along north-south and east-west gradients. Ancient DNA analysis reveals that this variant first appeared in South Asia during the historical and medieval periods through Steppe pastoralist-related gene flow. Interestingly, unlike in other worldwide populations, the LP prevalence is almost entirely explained by Steppe ancestry--not selection--in most contemporary South Asians. A notable exception is the only two pastoralist groups, Toda in South India and Gujjar in Pakistan, that have unexpectedly high frequencies of-13.910*T, comparable to estimates in Northern Europeans. By performing local ancestry inference, we find significant enrichment for Steppe pastoralist ancestry around the LCT locus in these two geographically-distant pastoralist groups, indicative of strong selection. Together, these findings highlight the complex role of ancestry and natural selection in shaping the prevalence of lactase persistence on the subcontinent.

evolutionary biology↗

bioRxiv2025

sedimix: A workflow for the analysis of hominin nuclear DNA sequences from sediments

SummarySediment DNA--the ability to extract DNA from archaeological sediments-- is an exciting new frontier in ancient DNA research, offering the potential to study individuals at a given archaeological site without destructive sampling. In recent years, several studies have demonstrated the promise of this approach by recovering hominin DNA from prehistoric sediments, including those dating back to the Middle or Late Pleistocene. However, a lack of open-source workflows for analysis of hominin sediment DNA samples poses a challenge for data processing and reproducibility of findings across studies. Here we introduce a snakemake workflow, sedimix, for processing genomic sequences from archaeological sediment DNA samples to identify hominin sequences and generate relevant summary statistics to assess the reliability of the pipeline. By performing simulations and comparing to published studies, we show that sedimix has high sensitivity and precision. sedimix offers a reliable and adaptable framework to aid in the analysis of sediment DNA datasets and improve reproducibility across studies. Availability and Implementationsedimix is available as an open-source software with the associated code and user manual available at https://github.com/jierui-cell/sedimix ContactJierui Xu (jierui.xu@berkeley.edu) Supplementary informationSupplementary data are available at Bioinformatics online

genetics↗

bioRxiv2024

Benchmarking for genotyping and imputation using degraded DNA for forensic applications across diverse populations

Advancements in sequencing and laboratory technologies have enabled forensic genetic analysis on increasingly low quality and degraded DNA samples. However, existing computational methods applied to genotyping and imputation for generating DNA profiles from degraded DNA have not been tested for forensic applications. Here we simulated sequencing data of varying qualities- coverage, fragment lengths, and deamination patterns-from forty individuals of diverse genetic ancestries. We used this dataset to test the performance of commonly used genotype and imputation methods (SAMtools, GATK, ATLAS, Beagle, and GLIMPSE) on five different SNP panels (MPS- plex, FORCE, two extended kinship panels, and the Human Origins array) that are used for forensic and population genetics applications. For genome mapping and variant calling with degraded DNA, we find use of parameters and methods (such as ATLAS) developed for ancient DNA analysis provides a marked improvement over conventional standards used for next generation sequencing analysis. We find that ATLAS outperforms GATK and SAMtools, achieving over 90% genotyping accuracy for the four largest SNP panels with coverages greater than 10X. For lower coverages, decreased concordance rates are correlated with increased rates of heterozygosity. Genotype refinement and imputation improve the accuracy at lower coverages by leveraging population reference data. For all five SNP panels, we find that using a population reference panel representative of worldwide populations (e.g., the 1000 Genomes Project) results in increased genotype accuracies across genetic ancestries, compared to ancestry-matched population reference panels. Importantly, we find that the low SNP density of commonly used forensics SNP panels can impact the reliability and performance of genotype refinement and imputation. This highlights a critical trade-off between enhancing privacy by using panels with fewer SNPs and maintaining the effectiveness of genomic tools. We provide benchmarks and recommendations for analyzing degraded DNA from diverse populations with widely used genomic methods in forensic casework. HighlightsO_LIBiallelic SNP panels: >92% genotyping accuracy for 10X data with ATLAS C_LIO_LIDegraded DNA impacts accuracy under sequencing depth of 10X coverage C_LIO_LIHigher accuracies across genetic ancestries achieved with a diverse reference panel C_LIO_LILeveraging population reference data is not applicable for small SNP panels C_LIO_LITrade-off between genotype accuracy and privacy when considering SNP panel size C_LI

genetics↗

bioRxiv2024

Neandertal ancestry through time: Insights from genomes of ancient and present-day humans

Gene flow from Neandertals has shaped the landscape of genetic and phenotypic variation in modern humans. We identify the location and size of introgressed Neandertal ancestry segments in more than 300 genomes spanning the last 50,000 years. We study how Neandertal ancestry is shared among individuals to infer the time and duration of the Neandertal gene flow. We find the correlation of Neandertal segment locations across individuals and their divergence to sequenced Neandertals, both support a model of single major Neandertal gene flow. Our catalog of introgressed segments through time confirms that most natural selection-positive and negative-on Neandertal ancestry variants occurred immediately after the gene flow, and provides new insights into how the contact with Neandertals shaped human origins and adaptation.

evolutionary biology↗

bioRxiv2024

50,000 years of Evolutionary History of India: Insights from ~2,700 Whole Genome Sequences

India has been underrepresented in whole genome sequencing studies. We generated 2,762 high coverage genomes from India--including individuals from most geographic regions, speakers of all major languages, and tribal and caste groups--providing a comprehensive survey of genetic variation in India. With these data, we reconstruct the evolutionary history of India through space and time at fine scales. We show that most Indians derive ancestry from three ancestral groups related to ancient Iranian farmers, Eurasian Steppe pastoralists and South Asian hunter-gatherers. We uncover a common source of Iranian-related ancestry from early Neolithic cultures of Central Asia into the ancestors of Ancestral South Indians (ASI), Ancestral North Indians (ANI), Austro-asiatic-related and East Asian-related groups in India. Following these admixtures, India experienced a major demographic shift towards endogamy, resulting in extensive homozygosity and identity-by-descent sharing among individuals. At deep time scales, Indians derive around 1-2% of their ancestry through gene flow from archaic hominins, Neanderthals and Denisovans. By assembling the surviving fragments of archaic ancestry in modern Indians, we recover [~]1.5 Gb (or 50%) of the introgressing Neanderthal and [~]0.6 Gb (or 20%) of the introgressing Denisovan genomes, more than any other previous archaic ancestry study. Moreover, Indians have the largest variation in Neanderthal ancestry, as well as the highest amount of population-specific Neanderthal segments among worldwide groups. Finally, we demonstrate that most of the genetic variation in Indians stems from a single major migration out of Africa that occurred around 50,000 years ago, with minimal contribution from earlier migration waves. Together, these analyses provide a detailed view of the population history of India and underscore the value of expanding genomic surveys to diverse groups outside Europe.

evolutionary biology↗

bioRxiv2023

The MUC19 gene in Denisovans, Neanderthals, and Modern Humans: An Evolutionary History of Recurrent Introgression and Natural Selection

We study the gene MUC19, for which some modern humans carry a Denisovan-like haplotype. MUC19 is a mucin, a glycoprotein that forms gels with various biological functions. We find diagnostic variants for the Denisovan-like MUC19 haplotype at high frequencies in admixed Latin American individuals, and at highest frequency in 23 ancient Indigenous American individuals, all predating population admixture with Europeans and Africans. We find that the Denisovan-like MUC19 haplotype is under positive selection and carries a higher copy number of a 30 base-pair variable number tandem repeat, and that copy numbers of this repeat are exceedingly high in American populations. Finally, some Neanderthals carry the Denisovan-like MUC19 haplotype, and that it was likely introgressed into human populations through Neanderthal introgression rather than Denisovan introgression. One-Sentence SummaryModern humans and Neanderthals carry a Denisovan variant of the MUC19 gene, which is under positive selection in populations of Indigenous American ancestry.

evolutionary biology↗

bioRxiv2022

Timing and causes of the evolution of the germline mutation spectrum in humans

Recent studies have suggested that the human germline mutation rate and spectrum evolve rapidly. Variation in generation time has been linked to these changes, though its contribution remains unclear. We develop a framework to characterize temporal changes in polymorphisms within and between populations, while controlling for the effects of natural selection and biased gene conversion. Application to the 1000 Genomes Project dataset reveals multiple independent changes that arose after the split of continental groups, including a previously reported, transient elevation in TCC>TTC mutations in Europeans and novel signals of divergence in C>G and T>A mutation rates among population samples. We also find a significant difference between groups sampled in and outside of Africa, in old T>C polymorphisms that predate the out-of-Africa migration. This surprising signal is driven by TpG>CpG mutations, and stems in part from mis-polarized CpG transitions, which are more likely to undergo recurrent mutations. Finally, by relating the mutation spectrum of polymorphisms to parental age effects on de novo mutations, we show that plausible changes in the generation time cannot explain the patterns observed for different mutation types jointly. Thus, other factors--genetic modifiers or environmental exposures--must have had a non-negligible impact on the human mutation landscape.

evolutionary biology↗

bioRxiv2022

Reconstructing the spatiotemporal patterns of admixture during the European Holocene using a novel genomic dating method

Recent studies have shown that gene flow or admixture has been pervasive throughout human history. While several methods exist for dating admixture in contemporary populations, they are not suitable for sparse, low coverage data available from ancient specimens. To overcome this limitation, we developed DATES that leverages ancestry covariance patterns across the genome of a single individual to infer the timing of admixture. By performing simulations, we show that DATES provides reliable results under a range of demographic scenarios and outperforms available methods for ancient DNA applications. We apply DATES to ~1,100 ancient genomes to reconstruct gene flow events during the European Holocene. Present-day Europeans derive ancestry from three distinct groups, local Mesolithic hunter-gatherers, Anatolian farmers, and Yamnaya Steppe pastoralists. These ancestral groups were themselves admixed. By studying the formation of Anatolian farmers, we infer that the gene flow related to Iranian Neolithic farmers occurred no later than 9,600 BCE, predating agriculture in Anatolia. We estimate the early Steppe pastoralist groups genetically formed more than a millennium before the start of steppe pastoralism, providing new insights about the history of proto-Yamnaya cultures and the origin of Indo-European languages. Using ancient genomes across sixteen regions in Europe, we provide a detailed chronology of the Neolithization across Europe that occurred from ~6,400-4,300 BCE. This movement was followed by a rapid spread of steppe ancestry from ~3,200-2,500 BCE. Our analyses highlight the power of genomic dating methods to elucidate the legacy of human migrations, providing insights complementary to archaeological and linguistic evidence. SignificanceThe European continent was subject to two major migrations during the Holocene: the movement of Near Eastern farmers during the Neolithic and the migration of Steppe pastoralists during the Bronze Age. To understand the timing and dynamics of these movements, we developed DATES that leverages ancestry covariance patterns across the genome of a single individual to infer the timing of admixture. Using ~1,100 ancient genomes spanning ~8,000-350 BCE, we reconstruct the chronology of the formation of the ancestral populations and the fine-scale details of the spread of Neolithic farming and Steppe pastoralist-related ancestry to Europe. Our analysis demonstrates the power of genomic dating methods to provide an independent and complementary timeline of population origins and movements using genetic data.

evolutionary biology↗

bioRxiv2021

Mutationathon: towards standardization in estimates of pedigree-based germline mutation rates

In the past decade, several studies have estimated the human per-generation germline mutation rate using large pedigrees. More recently, estimates for various non-human species have been published. However, methodological differences among studies in detecting germline mutations and estimating mutation rates make direct comparisons difficult. Here, we describe the many different steps involved in estimating pedigree-based mutation rates, including sampling, sequencing, mapping, variant calling, filtering, and how to appropriately account for false-positive and false-negative rates. For each step, we review the different methods and parameter choices that have been used in the recent literature. Additionally, we present the results from a "Mutationathon", a competition organized among five research labs to compare germline mutation rate estimates for a single pedigree of rhesus macaques. We report almost a two-fold variation in the final estimated rate among groups using different post-alignment processing, calling, and filtering criteria and provide details into the sources of variation across studies. Though the difference among estimates is not statistically significant, this discrepancy emphasizes the need for standardized methods in mutation rate estimations and the difficulty in comparing rates from different studies. Finally, this work aims to provide guidelines for computational and statistical benchmarks for future studies interested in identifying germline mutations from pedigrees.

evolutionary biology↗

bioRxiv2020

Reconstructing the history of founder events using genome-wide patterns of allele sharing across individuals

Founder events play a critical role in shaping genetic diversity, impacting the fitness of a species and disease risk in humans. Yet our understanding of the prevalence and distribution of founder events in humans and other species remains incomplete, as most existing methods for characterizing founder events require large sample sizes or phased genomes. To learn about the frequency and evolutionary history of founder events, we introduce ASCEND (Allele Sharing Correlation for the Estimation of Non-equilibrium Demography), a flexible two-locus method to infer the age and strength of founder events. This method uses the correlation in allele sharing across the genome between pairs of individuals to recover signatures of past bottlenecks. By performing coalescent simulations, we show that ASCEND can reliably estimate the parameters of founder events under a range of demographic scenarios, with genotype or sequence data. We apply ASCEND to ~5,000 worldwide human samples (~3,500 present-day and ~1,500 ancient individuals), and ~1,000 domesticated dog samples. In both species, we find pervasive evidence of founder events in the recent past. In humans, over half of the populations surveyed in our study had evidence for a founder events in the past 10,000 years, associated with geographic isolation, modes of sustenance, and historical invasions and epidemics. We document that island populations have historically maintained lower population sizes than continental groups, ancient hunter-gatherers had stronger founder events than Neolithic Farmers or Steppe Pastoralists, and periods of epidemics such as smallpox were accompanied by major population crashes. Many present-day groups--including Central & South Americans, Oceanians and South Asians--have experienced founder events stronger than estimated in Ashkenazi Jews who have high rates of recessive diseases due to their history of founder events. In dogs, we uncovered extreme founder events in most groups, more than ten times stronger than the median strength of founder events in humans. These founder events occurred during the last 25 generations and are likely related to the establishment of dog breeds during Victorian times. Our results highlight a widespread history of founder events in humans and dogs, and provide insights about the demographic and cultural processes underlying these events.

evolutionary biology↗

bioRxiv2019

A comparison of humans and baboons suggests germline mutation rates do not track cell divisions

In humans, most germline mutations are inherited from the father. This observation is widely interpreted as resulting from the replication errors that accrue during spermatogenesis. If so, the male bias in mutation should be substantially lower in a closely related species with similar rates of spermatogonial stem cell divisions but a shorter mean age of reproduction. To test this hypothesis, we resequenced two 3-4 generation nuclear families (totaling 29 individuals) of olive baboons (Papio anubis), who reproduce at ~10 years of age on average. We inferred sex-specific mutation rates by analyzing the data in parallel with three three-generation human pedigrees (26 individuals). The mutation rate per generation in baboons is 0.55x10-8 per base pair, approximately half that of humans. Strikingly, however, the degree of male mutation bias is approximately 3:1, similar to that of humans; in fact, a similar male bias is seen across mammals that reproduce months, years or decades after birth. These results echo findings in humans that the male bias is stable with parental ages and cast further doubt on the assumption that germline mutations track cell divisions. Our mutation rate estimates for baboons raise a further puzzle in suggesting a divergence time between apes and Old World Monkeys of 67 My, too old to be consistent with the fossil record; reconciling them now requires not only a slowdown of the mutation rate per generation in humans but also in baboons.

evolutionary biology↗

bioRxiv2018

Overlooked roles of DNA damage and maternal age in generating human germline mutations

Although the textbook view is that most germline mutations arise from replication errors, when analyzing large de novo mutation datasets in humans, we find multiple lines of evidence that call that understanding into question. Notably, despite the drastic increase in the ratio of male to female germ cell divisions after the onset of spermatogenesis, even young fathers contribute three times more mutations than young mothers, and this ratio barely increases with parental ages. This surprising finding points to a substantial contribution of damage-induced mutations. Indeed, C to G transversions and CpG transitions, which together constitute one third of all mutations, show genomic distributions and sex-specific age dependencies indicative of doublestrand break repair and methylation-associated damage, respectively. Moreover, the data indicate that maternal age at conception influences the mutation rate both because of the accumulation of damage in oocytes and potentially through an influence on the number of postzygotic mutations.

genetics↗

bioRxiv2018

The Genomic Formation of South and Central Asia

The genetic formation of Central and South Asian populations has been unclear because of an absence of ancient DNA. To address this gap, we generated genome-wide data from 362 ancient individuals, including the first from eastern Iran, Turan (Uzbekistan, Turkmenistan, and Tajikistan), Bronze Age Kazakhstan, and South Asia. Our data reveal a complex set of genetic sources that ultimately combined to form the ancestry of South Asians today. We document a southward spread of genetic ancestry from the Eurasian Steppe, correlating with the archaeologically known expansion of pastoralist sites from the Steppe to Turan in the Middle Bronze Age (2300-1500 BCE). These Steppe communities mixed genetically with peoples of the Bactria Margiana Archaeological Complex (BMAC) whom they encountered in Turan (primarily descendants of earlier agriculturalists of Iran), but there is no evidence that the main BMAC population contributed genetically to later South Asians. Instead, Steppe communities integrated farther south throughout the 2nd millennium BCE, and we show that they mixed with a more southern population that we document at multiple sites as outlier individuals exhibiting a distinctive mixture of ancestry related to Iranian agriculturalists and South Asian hunter-gathers. We call this group Indus Periphery because they were found at sites in cultural contact with the Indus Valley Civilization (IVC) and along its northern fringe, and also because they were genetically similar to post-IVC groups in the Swat Valley of Pakistan. By co-analyzing ancient DNA and genomic data from diverse present-day South Asians, we show that Indus Periphery-related people are the single most important source of ancestry in South Asia--consistent with the idea that the Indus Periphery individuals are providing us with the first direct look at the ancestry of peoples of the IVC--and we develop a model for the formation of present-day South Asians in terms of the temporally and geographically proximate sources of Indus Periphery-related, Steppe, and local South Asian hunter-gatherer-related ancestry. Our results show how ancestry from the Steppe genetically linked Europe and South Asia in the Bronze Age, and identifies the populations that almost certainly were responsible for spreading Indo-European languages across much of Eurasia.\n\nOne Sentence SummaryGenome wide ancient DNA from 357 individuals from Central and South Asia sheds new light on the spread of Indo-European languages and parallels between the genetic history of two sub-continents, Europe and South Asia.

genomics↗