Alissa L. Severson’s research while affiliated with Stanford University and other places

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Publications (10)


Figure 3: Proportion of autosomal and X-chromosomal ROH and IBD in each population. (A) ROH. (B) IBD. Populations are arranged in decreasing order by the proportion of the X-chromosomal genome lying in ROH.
Modeling the effects of consanguinity on autosomal and X-chromosomal runs of homozygosity and identity-by-descent sharing
  • Article
  • Full-text available

November 2023

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36 Reads

G3 Genes Genomes Genetics

Daniel J Cotter

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Alissa L Severson

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Jonathan T L Kang

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[...]

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Noah A Rosenberg

Runs of homozygosity (ROH) and identity-by-descent (IBD) sharing can be studied in diploid coalescent models by noting that ROH and IBD-sharing at a genomic site are predicted to be inversely related to coalescence times—which in turn can be mathematically obtained in terms of parameters describing consanguinity rates. Comparing autosomal and X-chromosomal coalescent models, we consider ROH and IBD-sharing in relation to consanguinity that proceeds via multiple forms of first-cousin mating. We predict that across populations with different levels of consanguinity, (1) in a manner that is qualitatively parallel to the increase of autosomal IBD-sharing with autosomal ROH, X-chromosomal IBD-sharing increases with X-chromosomal ROH, owing to the dependence of both quantities on consanguinity levels; (2) even in the absence of consanguinity, X-chromosomal ROH and IBD-sharing levels exceed corresponding values for the autosomes, owing to the smaller population size and lower coalescence time for the X chromosome than for autosomes; (3) with matrilateral consanguinity, the relative increase in ROH and IBD-sharing on the X chromosome compared to the autosomes is greater than in the absence of consanguinity. Examining genome-wide SNPs in human populations for which consanguinity levels have been estimated, we find that autosomal and X-chromosomal ROH and IBD-sharing levels generally accord with the predictions. We find that each 1% increase in autosomal ROH is associated with an increase of 2.1% in X-chromosomal ROH, and each 1% increase in autosomal IBD-sharing is associated with an increase of 1.6% in X-chromosomal IBD-sharing. For each calculation, particularly for ROH, the estimate is reasonably close to the increase of 2% predicted by the population-size difference between autosomes and X chromosomes. The results support the utility of coalescent models for understanding patterns of genomic sharing and their dependence on sex-biased processes.

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

August 2022

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3 Reads

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2 Citations

Theoretical Population Biology

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.


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

May 2022

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7 Reads

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2 Citations

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.


Fig. 1. Identifiers for ancient and present-day individuals used in this study. (A) Map of ancient and present-day individuals, colored by regional grouping. The inset shows the new individuals from the San Francisco Bay Area (blue) and the surrounding groups. (B) Dates of ancient individuals included in the dataset.
Fig. 7. Membership in the blue cluster in the K = 5 cluster analysis in Fig. 5, divided by one minus membership in the red cluster, for present-day populations from California and Mexico. For each individual, the proportion is calculated as the membership fraction in the blue cluster divided by the total fraction of membership in the blue, purple, light orange, and dark orange clusters. Individual values and boxplots are shown.
Ancient and modern genomics of the Ohlone Indigenous population of California

March 2022

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248 Reads

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16 Citations

Proceedings of the National Academy of Sciences

Significance California supports a high cultural and linguistic diversity of Indigenous peoples. In a partnership of researchers with the Muwekma Ohlone tribe, we studied genomes of eight present-day tribal members and 12 ancient individuals from two archaeological sites in the San Francisco Bay Area, spanning ∼2,000 y. We find that compared to genomes of Indigenous individuals from throughout the Americas, the 12 ancient individuals are most genetically similar to ancient individuals from Southern California, and that despite spanning a large time period, they share distinctive ancestry. This ancestry is also shared with present-day tribal members, providing evidence of genetic continuity between past and present Indigenous individuals in the region, in contrast to some popular reconstructions based on archaeological and linguistic information.


Fig. 1. Performance of LocalNgsRelate, Albrechtsen et al. (2009) and hap-IBD for five pairs of individuals at different sequencing depths. Performance was assessed by comparing the IBD state assigned by each method when applied to NGS data to the IBD state assigned by Albrechtsen et al. (2009) applied to high-quality genotype data for the same individuals
LocalNgsRelate: a software tool for inferring IBD sharing along the genome between pairs of individuals from low-depth NGS data

October 2021

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26 Reads

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7 Citations

Bioinformatics

Motivation Inference of Identity-by-descent (IBD) sharing along the genome between pairs of individuals has important uses. But all existing inference methods are based on genotypes, which is not ideal for low-depth Next Generation Sequencing (NGS) data from which genotypes can only be called with high uncertainty. Results We present a new probabilistic software tool, LocalNgsRelate, for inferring IBD sharing along the genome between pairs of individuals from low-depth NGS data. Its inference is based on genotype likelihoods instead of genotypes, and thereby it takes the uncertainty of the genotype calling into account. Using real data from the 1000 Genomes project, we show that LocalNgsRelate provides more accurate IBD inference for low-depth NGS data than two state-of-the-art genotype based methods, Albrechtsen et al. (2009) and hap-IBD. We also show that the method works well for NGS data down to a depth of 2X. Availability LocalNgsRelate is freely available at https://github.com/idamoltke/LocalNgsRelate Supplementary Data Supplementary data are available at Bioinformatics online.


The effect of consanguinity on coalescence times on the X chromosome

April 2021

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14 Reads

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7 Citations

Theoretical Population Biology

Consanguineous unions increase the frequency at which identical genomic segments are inherited along separate paths of descent, decreasing coalescence times for pairs of alleles drawn from an individual who is the offspring of a consanguineous pair. For an autosomal locus, it has recently been shown that the mean time to the most recent common ancestor (TMRCA) for two alleles in the same individual and the mean TMRCA for two alleles in two separate individuals both decrease with increasing consanguinity in a population. Here, we extend this analysis to the X chromosome, considering X-chromosomal coalescence times under a coalescent model with diploid, male-female mating pairs. We examine four possible first-cousin mating schemes that are equivalent in their effects on autosomes, but that have differing effects on the X chromosome: patrilateral-parallel, patrilateral-cross, matrilateral-parallel, and matrilateral-cross. In each mating model, we calculate mean TMRCA for X-chromosomal alleles sampled either within or between individuals. We describe a consanguinity effect on X-chromosomal TMRCA that differs from the autosomal pattern under matrilateral but not under patrilateral first-cousin mating. For matrilateral first cousins, the effect of consanguinity in reducing TMRCA is stronger on the X chromosome than on the autosomes, with an increased effect of parallel-cousin mating compared to cross-cousin mating. The theoretical computations support the utility of the model in understanding patterns of genomic sharing on the X chromosome.


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

March 2021

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2 Reads

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8 Citations

Theoretical Population Biology

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.


Figure 3: The cumulative distributions of coalescence times within (T ) and between (V ) individuals as functions of generations t and the fraction c0 of sib mating pairs. (A) P(T ≤ t), eq. 27. (B) P(V ≤ t), eq. 28.
Figure 7: Limiting cumulative distribution functions for T and V , eqs. 45 and 46, and simulated exact cumulative distributions, for 25 generations. The plots consider a range of values for the number of mating pairs (N ), fixing the degree of cousin relationship at n = 1 and the consanguinity rate at c1 = 0.2. (A) T , N = 10. (B) T , N = 100. (C) T , N = 1000. (D) T , N = 10000. (E) V , N = 10. (F) V , N = 100. (G) V , N = 1000. (H) V , N = 10000.
Variance and limiting distribution of coalescence times in a diploid model of a consanguineous population

July 2020

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29 Reads

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1 Citation

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.



The Effect of Consanguinity on Between-Individual Identity-By-Descent Sharing

March 2019

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55 Reads

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20 Citations

Genetics

Consanguineous unions increase the rate at which identical genomic segments are paired within individuals to produce runs of homozygosity (ROH). The extent to which such unions affect identity-by-descent (IBD) genomic sharing between rather than within individuals in a population, however, is not immediately evident from within-individual ROH levels. Using the fact that the time to the most recent common ancestor [Formula: see text] for a pair of genomes at a specific locus is inversely related to the extent of IBD sharing between the genomes in the neighborhood of the locus, we study IBD sharing for a pair of genomes sampled either within the same individual or in different individuals. We develop a coalescent model for a set of mating pairs in a diploid population, treating the fraction of consanguineous unions as a parameter. Considering mating models that include unions between sibs, first cousins, and nth cousins, we determine the effect of the consanguinity rate on the mean [Formula: see text] for pairs of lineages sampled either within the same individual or in different individuals. The results indicate that consanguinity not only increases ROH sharing between the two genomes within an individual, it also increases IBD sharing between individuals in the population, the magnitude of the effect increasing with the kinship coefficient of the type of consanguineous union. Considering computations of ROH and between-individual IBD in Jewish populations whose consanguinity rates have been estimated from demographic data, we find that, in accord with the theoretical results, increases in consanguinity and ROH levels inflate levels of IBD sharing between individuals in a population. The results contribute more generally to the interpretation of runs of homozygosity, IBD sharing between individuals, and the relationship between ROH and IBD.

Citations (9)


... ROH and IBD-with consanguinity that proceeds via matrilateral first-cousin mating reducing X-chromosomal 47 coalescence times to a greater extent than patrilateral first-cousin mating (Cotter et al., 2021(Cotter et al., , 2022. 48 Here, we study the connections between autosomal and X-chromosomal T M RCA and features of X-chromosomal 49 and autosomal ROH and IBD. ...

Reference:

Modeling the effects of consanguinity on autosomal and X-chromosomal runs of homozygosity and identity-by-descent sharing
Limiting distribution of X-chromosomal coalescence times under first-cousin consanguineous mating
  • Citing Article
  • August 2022

Theoretical Population Biology

... The progeny of a consanguineous union is predicted to have considerable portions of their genomes shared between their two genomic copies owing to the fact that an identical genomic segment can be inherited along both maternal and paternal lines. Empirical genetic studies have identified many populations in which individuals carry long runs of homozygosity (ROH), attributable in large part to consanguinity practices (McQuillan et al. 2008;Pemberton et al. 2012;Ceballos et al. 2018;Cotter et al. 2022). Two continuous stretches, identical by descent (IBD) of homozygous segments of genotypes (haplotypes) of a common ancestor in a person inherited from both the parents are termed as ROH, an indicator of genomic autozygosity (Gibson et al. 2006). ...

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

... 88 Everyone should stop and rethink if and how, or at what costs, we feed the media(clicks), good or bad journalism, or political interests and populism. 89 Death threats are no longer foreign for historians and archaeologists; biomolecular results can be used as evidence in the court for federal recognition 90 ; biological proof has become part of identity politics reducing ethnicity into a biologically (static) category, yet history is disturbingly full of examples where similar scientific findings have been used as arguments against the principles of human rights and humanism on a wider scale. 91 Information is power, but we should be more careful how we use this power and what impact it has on the wider public. ...

Ancient and modern genomics of the Ohlone Indigenous population of California

Proceedings of the National Academy of Sciences

... f3-statistics were calculated using admixtools2 (Maier et al. 2023;Patterson et al. 2012) with the haploid panel. We also used LocalNgsRelate (Severson, Korneliussen, and Moltke 2021) to infer identity-bydescent (IBD) sharing along the genome between the Zanzibar and other African leopards, using default parameters. ...

LocalNgsRelate: a software tool for inferring IBD sharing along the genome between pairs of individuals from low-depth NGS data

Bioinformatics

... Campbell (2015) and Severson et al. (2019) studied expected coalescence times for given rates of mating between cousins of varying degree, including sibs or "0-degree cousins". Severson et al. (2021) and Cotter et al. (2021) extended these models and applied the separation-of-timescales result of Möhle (1998) to obtain the limiting distributions of coalescence times in the unconditional case. Based on the results we presented here, we would expect to see some effects of the population pedigree in conditional coalescent processes for these and other forms of inbreeding. ...

The effect of consanguinity on coalescence times on the X chromosome
  • Citing Article
  • April 2021

Theoretical Population Biology

... Campbell (2015) and Severson et al. (2019) studied expected coalescence times for given rates of mating between cousins of varying degree, including sibs or "0-degree cousins". Severson et al. (2021) and Cotter et al. (2021) extended these models and applied the separation-of-timescales result of Möhle (1998) to obtain the limiting distributions of coalescence times in the unconditional case. Based on the results we presented here, we would expect to see some effects of the population pedigree in conditional coalescent processes for these and other forms of inbreeding. ...

Variance and limiting distribution of coalescence times in a diploid model of a consanguineous population
  • Citing Article
  • March 2021

Theoretical Population Biology

... Supplementary Figure 19 illustrates the importance of considering not only average kinship between spouses but also historical Ne when evaluating the proportion of the genome covered by ROHs of different lengths (the 'ROH footprint'); the Ne has a major influence on the expected footprint of ROHs < 25cM, but much less on ROHs longer than this, since those are primarily due to mating between close relatives. We ran the model from 62 using the Ne estimates from IBDNe ( Figure 3b) as input, varying the average spousal kinship (see Methods). Figure 5 compares the observed ROH and IBD footprints to those expected under the models with different parameters. ...

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

... Several articles have pointed out the shortfall of IDEA in the theoretical biology community [43,98,99]. Evidence suggests theoreticians are an impactful yet privileged group lacking diversity (e.g., [100]). This lack of diversity may partly stem from the smaller size of the theoretical community or its concentration primarily at top institutes in wealthy nations (c.f., [101]). ...

Analysis of author gender in TPB, 1991–2018
  • Citing Article
  • April 2019

Theoretical Population Biology

... It would be of interest to understand the pedigree effects of inbreeding generally in the conditional case. Campbell (2015) and Severson et al. (2019) studied expected coalescence times for given rates of mating between cousins of varying degree, including sibs or "0-degree cousins". Severson et al. (2021) and Cotter et al. (2021) extended these models and applied the separation-of-timescales result of Möhle (1998) to obtain the limiting distributions of coalescence times in the unconditional case. ...

The Effect of Consanguinity on Between-Individual Identity-By-Descent Sharing
  • Citing Article
  • March 2019

Genetics