Biology subjects

Carmi, S.

Publications and source records attributed to Carmi, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Forensic investigative genetic genealogy match rate estimated from a nation-wide population register

Forensic investigative genetic genealogy (FIGG) is a revolutionary method in forensic genetics, whereby genetic relatives of an unknown target person are detected in direct-to-consumer genomic databases; the family trees of these relatives are then reconstructed to suggest candidates for the target person. Despite recent successes, the full potential of the technology has not yet been systematically evaluated at the scale of an entire country. To estimate the proportion of FIGG cases where a genetic relative is detected in the database (the "match rate"), we used the Israeli population register, covering all past and present citizens. After extensive quality control, the register included 12.4 million individuals, among them 10.4 million alive. We simulated genomic databases by randomly selecting subsets of predefined sizes of the live adult population. With a database covering 1% of the population, we estimate that FIGG would detect at least one relative of fifth degree (e.g., a second cousin) or closer for about 25% of the population, and at least two relatives for 9% of the population. A database covering 5% of the population would find at least one relative of third degree (e.g., a first cousin) or closer for half the population. More distant relatives are rarely identified in the register, likely due to its limited time depth. Our results provide the first country-wide direct estimates for the utility of FIGG in generating investigative leads.

genetics↗

bioRxiv2026

Whole-genome sequencing of a mid-20th-century femur from central Israel in an open missing-person case

Genome-wide technologies can generate investigative leads in cold cases by determining the genetic ancestry of the forensic sample. Increasingly, DNA extraction and whole-genome sequencing or genotyping are being used to analyze early or middle-20th century skeletal remains. Here, we present the first case, to our knowledge, of whole-genome sequencing of a middle-20th-century bone sample from the Middle East. A femur discovered in a cave in Central Israel was proposed to belong to a person of Ashkenazi Jewish ancestry who was missing since 1948. Following DNA extraction and single-stranded library preparation, whole-genome sequencing generated nearly 500 million reads. However, only 0.5% of the reads mapped to the human genome, providing depth of coverage of 0.07x. After quality control and male sex inference, ancestry assignment was performed using principal components and ADMIXTURE analyses. The results suggested that the genome definitively belonged to a person of Arab ancestry, refuting the hypothesis of an Ashkenazi Jewish origin.

genetics↗

bioRxiv2025

Maternal age and genome-wide failure of meiotic recombination are associated with triploid conceptions in humans

Triploid and haploid conceptions are not viable and are a common occurrence in humans, where they account for 10% of all pregnancy losses. Despite the parent-of-origin being important in the etiology of the pregnancy, our knowledge of their causes is limited, especially at the point of conception. Using a dataset of 96,660 biopsies and a validation dataset of 44,324 from human blastocysts embryos generated by intra-cytoplasmic sperm injection (ICSI), we estimate that 1.1% of human conceptions (n=1,063) contain extra or missing chromosome sets in zygotes. We identify a maternal age effect, with a 1.059 per year increased risk in triploidy/haploidy (p=0.0008). In 0.03% of couples, we identified three or more triploid/haploid embryos, suggesting a personal risk effect (p=0.03). Genotype analysis of 55 triploid embryo biopsies and their parents show that one third of maternal triploid conceptions originate in meiosis I and two thirds in meiosis II. Seven of these embryos are inferred to have entirely failed to initiate meiotic recombination genome-wide, suggesting that human oocytes with pervasive meiotic recombination failure that are formed during fetal development are capable of ovulation in adult life. Finally, we identify a new type of genome-wide maternal isodiploidy (two maternal chromosome sets) in 0.05% of embryos (41 of 74,009). Collectively, our findings shed light on the biology of meiosis and the formation of human oocytes with the number of chromosome sets.

genetics↗

bioRxiv2024

Estimating effective population size trajectories from time-series Identity-by-Descent (IBD) segments

Long, identical haplotypes shared between pairs of individuals, known as identity-by-descent (IBD) segments, result from recently shared co-ancestry. Various methods have been developed to utilize IBD sharing for demographic inference in contemporary DNA data. Recent methodological advances have enabled the screening for IBD in ancient DNA (aDNA) data, making demographic inference based on IBD also possible for aDNA. However, aDNA data typically have varying sampling times, but most demographic inference methods designed for modern data assume that sampling is contemporaneous. Here, we present TTNE (Time-Transect Ne), which models time-transect sampling to improve inference of recent effective population size trajectories. Using simulations, we show that utilizing IBD sharing in time series has increased resolution to infer recent fluctuations in effective population sizes compared to methods that only use contemporaneous samples. Finally, we developed an approach for estimating and modeling IBD detection errors in empirical IBD analysis. To showcase the practical utility of TTNE, we applied it to two time transects of ancient genomes, individuals associated with the Corded Ware Culture (CWC) and Medieval England. In both cases, we found evidence of a growing population, a signal consistent with archaeological records.

evolutionary biology↗

bioRxiv2024

Predicting the direction of phenotypic difference

Predicting phenotypes from genomic data is a key goal in genetics, but for most complex phenotypes, predictions are hampered by incomplete genotype-to-phenotype mapping. Here, we describe a more attainable approach than quantitative predictions, which is aimed at qualitatively predicting phenotypic differences. Despite incomplete genotype-to-phenotype mapping, we show that it is relatively easy to determine which of two individuals has a greater phenotypic value. This question is central in many scenarios, e.g., comparing disease risk between individuals, the yield of crop strains, or the anatomy of extinct vs extant species. To evaluate prediction accuracy, i.e., the probability that the individual with the greater predicted phenotype indeed has a greater phenotypic value, we developed an estimator of the ratio between known and unknown effects on the phenotype. We evaluated prediction accuracy using human data from tens of thousands of individuals from either the same family or the same population, as well as data from different species. We found that, in many cases, even when only a small fraction of the loci affecting a phenotype is known, the individual with the greater phenotypic value can be identified with over 90% accuracy. Our approach also circumvents some of the limitations in transferring genetic association results across populations. Overall, we introduce an approach that enables accurate predictions of key information on phenotypes -- the direction of phenotypic difference -- and suggest that more phenotypic information can be extracted from genomic data than previously appreciated.

genetics↗

bioRxiv2022

Genetic estimates of the initial peopling of Polynesian islands actually reflect later inter-island contacts

The timing of the initial peopling of the Polynesian islands remains highly debated. Suggested dates are primarily based on archaeological evidence and differ by several hundred years. Ioannidis et al. [2021] used genome-wide data from 430 modern individuals from 21 Pacific islands to obtain genetic estimates. Their results supported late settlement dates, e.g. approximately 1200 CE for Rapa Nui. However, when investigating the underlying model we found that the genetic estimator used by Ioannidis et al. [2021] is biased to be about 300 years too old. Correcting for this bias gives genetic settlement dates that are more recent than any dates consistent with archaeological records, as radiocarbon dating of human-modified artifacts shows settlement definitively earlier than the bias-corrected genetic estimates. These too-recent estimates can only be explained by substantial gene flow between islands after their initial settlements. Therefore, contacts attested by archaeological and linguistic evidence [Kirch, 2021] must have been accompanied also by demographically significant movement of people. This gene flow well after the initial settlements was not modelled by Ioannidis et al. [2021] and challenges their interpretation that carving anthropomorphic stone statues was spread during initial settlements of islands. Instead, the distribution of this cultural practice likely reflects later inter-island exchanges, as suggested earlier [Kirch, 2017].

genetics↗

bioRxiv2022

Genome-wide data from medieval German Jews show that the Ashkenazi founder event pre-dated the 14th century

We report genome-wide data for 33 Ashkenazi Jews (AJ), dated to the 14th century, following a salvage excavation at the medieval Jewish cemetery of Erfurt, Germany. The Erfurt individuals are genetically similar to modern AJ and have substantial Southern European ancestry, but they show more variability in Eastern European-related ancestry than modern AJ. A third of the Erfurt individuals carried the same nearly-AJ-specific mitochondrial haplogroup and eight carried pathogenic variants known to affect AJ today. These observations, together with high levels of runs of homozygosity, suggest that the Erfurt community had already experienced the major reduction in size that affected modern AJ. However, the Erfurt bottleneck was more severe, implying substructure in medieval AJ. Together, our results suggest that the AJ founder event and the acquisition of the main sources of ancestry pre-dated the 14th century and highlight late medieval genetic heterogeneity no longer present in modern AJ.

genetics↗

bioRxiv2022

Limiting distribution of X-chromosomal coalescence times under first-cousin consanguineous mating

By providing additional opportunities for coalescence within families, the presence of consanguineous unions in a population reduces coalescence times relative to non-consanguineous populations. First-cousin consanguinity can take one of six forms differing in the configuration of sexes in the pedigree of the male and female cousins who join in a consanguineous union: patrilateral parallel, patrilateral cross, matrilateral parallel, matrilateral cross, bilateral parallel, and bilateral cross. Considering populations with each of the six types of first-cousin consanguinity individually and a population with a mixture of the four unilateral types, we examine coalescent models of consanguinity. We previously computed, for first-cousin consanguinity models, the mean coalescence time for X-chromosomal loci and the limiting distribution of coalescence times for autosomal loci. Here, we use the separation-of-time-scales approach to obtain the limiting distribution of coalescence times for X-chromosomal loci. This limiting distribution has an instantaneous coalescence probability that depends on the probability that a union is consanguineous; lineages that do not coalesce instantaneously coalesce according to an exponential distribution. We study the effects on the coalescence time distribution of the type of first-cousin consanguinity, showing that patrilateral-parallel and patrilateral-cross consanguinity have no effect on X-chromosomal coalescence time distributions and that matrilateral-parallel consanguinity decreases coalescence times to a greater extent than does matrilateral-cross consanguinity.

genetics↗

bioRxiv2021

Cascade screening following a polygenic risk score test: what is the disease risk of a sibling conditional on a high score of a proband?

Polygenic risk scores (PRSs) for predicting disease risk have become increasingly accurate, leading to rising popularity of PRS tests. Consider an individual whose PRS test has placed him/her at the top q-quantile of genetic risk. Recently, Reid et al. (Circ Genom Precis Med. 2021;14:e003262) have investigated whether such a finding should motivate cascade screening in the probands siblings. Specifically, using data from the UK biobank, Reid et al. computed the empirical probability of a sibling of the proband to also have a PRS at the top q-quantile. In this short note, I use the liability threshold model to compute this probability analytically (for either a sibling of the proband or for a more distant relative), showing excellent agreement with the empirical results of Reid et al., including that this probability is disease-independent. Further, I compute the probability of the relative of the proband to be affected, as a function of the quantile threshold q, the proportion of variance explained by the score, and the disease prevalence.

genetics↗

bioRxiv2020

The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects

The number and distribution of recessive alleles in the population for various diseases are not known at genome-wide-scale. Based on 6447 exome-sequences of healthy, genetically-unrelated Europeans of two distinct ancestries, we estimate that every individual is a carrier of at least 2 pathogenic variants in currently known autosomal recessive (AR) genes, and that 0.8-1% of European couples are at-risk of having a child affected with a severe AR genetic disorder. This risk is 16.5-fold higher for first cousins, but is significantly more increased for skeletal disorders and intellectual disabilities due to their distinct genetic architecture.

genetics↗

bioRxiv2020

Utility of polygenic embryo screening for disease depends on the selection strategy

Polygenic risk scores (PRSs) have been offered since 2019 to screen in vitro fertilization embryos for genetic liability to adult diseases, despite a lack of comprehensive modeling of expected outcomes. Here we predict, based on the liability threshold model, the expected reduction in complex disease risk following polygenic embryo screening for a single disease. Our main finding is that a strong determinant of the potential utility of such screening is the selection strategy, a factor that has not been previously studied. Specifically, when only embryos with a very high PRS are excluded, the achieved risk reduction is minimal. In contrast, selecting the embryo with the lowest PRS can lead to substantial relative risk reductions, given a sufficient number of viable embryos. For example, a relative risk reduction of {approx}50% for schizophrenia can be achieved by selecting the embryo with the lowest PRS out of five viable embryos. We systematically examine the impact of several factors on the utility of screening, including the variance explained by the PRS, the number of embryos, the disease prevalence, the parental PRSs, and the parental disease status. When quantifying the utility, we consider both relative and absolute risk reductions, as well as population-averaged and per-couple risk reductions. We also examine the risk of pleiotropic effects. Finally, we confirm our theoretical predictions by simulating "virtual" couples and offspring based on real genomes from schizophrenia and Crohns disease case-control studies. We discuss the assumptions and limitations of our model, as well as the potential emerging ethical concerns.

genetics↗

bioRxiv2020

Relative matching using low coverage sequencing

Finding familial relatives using DNA has multiple applications, in genetic genealogy, population genetics, and forensics. So far, most relative matching algorithms rely on detecting identity-by-descent (IBD) segments with high quality genotype data. Recently, low coverage sequencing (LCS) has received growing attention as a promising cost-effective method to ascertain genomic information. However, with higher error rates, it is unclear whether existing IBD detection can work on LCS datasets. Here, we developed and tested a framework for relative matching using sequencing with 1x coverage (1xLCS). We started by exploring the error characteristics of this method compared to array data. Our results show that after some optimization 1xLCS can exhibit the same genotyping discordance rates as the discordance between two array platforms. Using this observation, we developed a hybrid framework for relative matching and tuned this framework with >2,700 pairs of confirmed genealogical relatives that were genotyped using heterogenous datasets. We then obtained array and 1xLCS on 19 samples and use our framework to find relatives in a database of over 3 million individuals. The total length of shared segments obtained by 1xLCS was virtually indistinguishable to genotyping arrays for matches with a total sharing >200cM (second cousins or closer). For more distant relatives, as long as those were detected by both technologies, the total length obtained by LCS and by genotyping arrays was highly correlated, with no evidence of over- or underestimation. Taken together, our results show that 1xLCS can be a valid alternative to arrays for relative matching, opening the possibility for further democratization of genomic data.

bioinformatics↗

bioRxiv2020

Fine-scale population structure and demographic history of British Pakistanis

Previous genetic and public health research in the Pakistani population has focused on the role of consanguinity in increasing recessive disease risk, but little is known about its recent population history or the effects of endogamy. Here, we investigate fine-scale population structure, history and consanguinity patterns using genetic and questionnaire data from >4,000 British Pakistani individuals, mostly with roots in Azad Kashmir and Punjab. We reveal strong recent population structure driven by the biraderi social stratification system. We find that all subgroups have had low effective population sizes (Ne) over the last 50 generations, with some showing a decrease in Ne 15-20 generations ago that has resulted in extensive identity-by-descent sharing and increased homozygosity. Using new theory, we show that the footprint of regions of homozygosity in the two largest subgroups is about twice that expected naively based on the self-reported consanguinity rates and the inferred historical Ne trajectory. These results demonstrate the impact of the cultural practices of endogamy and consanguinity on population structure and genomic diversity in British Pakistanis, and have important implications for medical genetic studies.

genomics↗

bioRxiv2020

Variance and limiting distribution of coalescence times in a diploid model of a consanguineous population

Recent modeling studies interested in runs of homozygosity (ROH) and identity by descent (IBD) have sought to connect these properties of genomic sharing to pairwise coalescence times. Here, we examine a variety of features of pairwise coalescence times in models that consider consanguinity. In particular, we extend a recent diploid analysis of mean coalescence times for lineage pairs within and between individuals in a consanguineous population to derive the variance of coalescence times, studying its dependence on the frequency of consanguinity and the kinship coefficient of consanguineous relationships. We also introduce a separation-of-time-scales approach that treats consanguinity models analogously to mathematically similar phenomena such as partial selfing, using this approach to obtain coalescence-time distributions. This approach shows that the consanguinity model behaves similarly to a standard coalescent, scaling population size by a factor 1 − 3c, where c represents the kinship coefficient of a randomly chosen mating pair. It provides the explanation for an earlier result describing mean coalescence time in the consanguinity model in terms of c. The results extend the potential to make predictions about ROH and IBD in relation to demographic parameters of diploid populations.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genetics↗

bioRxiv2019

Screening human embryos for polygenic traits has limited utility

Genome-wide association studies have led to the development of polygenic score (PS) predictors that explain increasing proportions of the variance in human complex traits. In parallel, progress in preimplantation genetic testing now allows genome-wide genotyping of embryos generated via in vitro fertilization (IVF). Jointly, these developments suggest the possibility of screening embryos for polygenic traits such as height or cognitive function. There are clear ethical, legal, and societal concerns regarding such a procedure, but these cannot be properly discussed in the absence of data on the expected outcomes of screening. Here, we use theory, simulations, and real data to evaluate the potential gain of PS-based embryo selection, defined as the expected difference in trait value between the top-scoring embryo and an average, unselected embryo. We observe that the gain increases very slowly with the number of embryos, but more rapidly with increased variance explained by the PS. Given currently available polygenic predictors and typical IVF yields, the average gain due to selection would be {approx}2.5cm if selecting for height, and {approx}2.5 IQ (intelligence quotient) points if selecting for cognitive function. These mean values are accompanied by wide confidence intervals; in real data drawn from nuclear families with up to 20 offspring each, we observe that the offspring with the highest PS for height was the tallest only in 25% of the families. We discuss prospects and limitations of PS-based embryo selection for the foreseeable future.

genetics↗

bioRxiv2019

A test for Hardy-Weinberg equilibrium on the X chromosome for sex-biased admixed populations

Genome-wide scans for deviations from Hardy-Weinberg equilibrium (HWE) are commonly applied to detect genotyping errors. In contrast to the autosomes, genotype frequencies on the X chromosome do not reach HWE within a single generation. Instead, if allele frequencies in males and females initially differ, they oscillate for a few generations towards equilibrium. Several populations world-wide have experienced recent sex-biased admixture, namely, their male and female founders differed in ancestry and thus in allele frequencies. Sex-biased admixture makes testing for HWE difficult on X, because deviations are naturally expected, even under random mating post-admixture and error-free genotyping. In this paper, we develop a likelihood ratio test and a{chi} 2 test that detect deviations from HWE on X while allowing for natural deviations due to sex-biased admixture. We demonstrate by simulations that our tests are powerful for detecting deviations due to non-random mating, while at the same time they do not reject the null under historical sex-biased admixture and random mating thereafter. We also demonstrate that when applied to 1000 Genomes project populations (e.g., as a quality control step), our tests reject fewer SNPs (among those showing frequency differences between the sexes) than other tests.

genetics↗

bioRxiv2018

FactorialHMM: Fast and exact inference in factorial hidden Markov models

MotivationHidden Markov models (HMMs) are powerful tools for modeling processes along the genome. In a standard genomic HMM, observations are drawn, at each genomic position, from a distribution whose parameters depend on a hidden state; the hidden states evolve along the genome as a Markov chain. Often, the hidden state is the Cartesian product of multiple processes, each evolving independently along the genome. Inference in these so-called Factorial HMMs has a naive running time that scales as the square of the number of possible states, which by itself increases exponentially with the number of subchains; such a running time scaling is impractical for many applications. While faster algorithms exist, there is no available implementation suitable for developing bioinformatics applications.\n\nResultsWe developed FactorialHMM, a Python package for fast exact inference in Factorial HMMs. Our package allows simulating either directly from the model or from the posterior distribution of states given the observations. Additionally, we allow the inference of all key quantities related to HMMs: (1) the (Viterbi) sequence of states with the highest posterior probability; (2) the likelihood of the data; and (3) the posterior probability (given all observations) of the marginal and pairwise state probabilities. The running time and space requirement of all procedures is linearithmic in the number of possible states. Our package is highly modular, providing the user with maximal flexibility for developing downstream applications.\n\nAvailabilityhttps://github.com/regevs/factorialhmm

bioinformatics↗

bioRxiv2018

Re-identification of genomic data using long range familial searches

Consumer genomics databases reached the scale of millions of individuals. Recently, law enforcement investigators have started to exploit some of these databases to find distant familial relatives, which can lead to a complete re-identification. Here, we leveraged genomic data of 600,000 individuals tested with consumer genomics to investigate the power of such long-range familial searches. We project that half of the searches with European-descent individuals will result with a third cousin or closer match and will provide a search space small enough to permit re-identification using common demographic identifiers. Moreover, in the near future, virtually any European-descent US person could be implicated by this technique. We propose a potential mitigation strategy based on cryptographic signature that can resolve the issue and discuss policy implications to human subject research.

genomics↗