purgeR: inbreeding and purging in pedigreed populations

SUMMARY: Inbreeding depression and genetic purging are important processes shaping the survivability and evolution of small populations. However, detecting purging is challenging in practice, in part because there are limited tools dedicated to it. I present a new R package to assist population analyses on detection and quantification of the inbreeding depression and genetic purging of biological fitness in pedigreed populations. It includes a collection of methods to estimate different measurements of inbreeding (Wright’s, partial and ancestral inbreeding coefficients) as well as purging parameters (purged inbreeding, and opportunity of purging coefficients). Additional functions are also included to estimate population parameters, allowing to contextualize inbreeding and purging these results in terms of the population demographic history. purgeR is a valuable tool to gain insight into processes related to inbreeding and purging, and to better understand fitness and inbreeding load evolution in small populations. AVAILABILITY AND IMPLEMENTATION: purgeR is an R package available at CRAN, and can be installed via install.packages(“purgeR”). Source code is maintained at a GitLab repository (https://gitlab.com/elcortegano/purgeR). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online

Evaluación de la purga genética en poblaciones de censo reducido

La depresión consanguínea puede ser decisiva para la extinción de poblaciones de censopequeño. Sin embargo, la consanguinidad también incrementa la selección contra losdeletéreos responsables de dicha depresión. A este incremento de la selección se ledenomina purga genética. Sus consecuencias pueden analizarse utilizando el modelo IP(García-Dorado 2012), que permite predecir la reducción del lastre de consanguinidad yde la depresión consanguínea atribuibles a la purga a través de un coeficiente deconsanguinidad purgado (g) que depende del coeficiente de purga (d).Hasta la fecha se ha publicado una única estima de d para la purga en condiciones nocompetitivas, obtenida en un experimento con Drosophila (Bersabé & García-Dorado2013). Sin embargo, existen evidencias de que d puede ser mayor en las condiciones máscompetitivas de las poblaciones silvestres que en cautividad. Además, es necesarioestimar d en las propias poblaciones amenazadas de interés, donde no es posible el diseñoexperimental pero a menudo se dispone de medidas de la eficacia individual y registrosgenealógicos..

Highly pleiotropic variants of human traits are enriched in genomic regions with strong background selection

Recent studies have shown the ubiquity of pleiotropy for variants affecting human complex traits. These studies also show that rare variants tend to be less pleiotropic than common ones, suggesting that purifying natural selection acts against highly pleiotropic variants of large effect. Here, we investigate the mean frequency, effect size and recombination rate associated with pleiotropic variants, and focus particularly on whether highly pleiotropic variants are enriched in regions with putative strong background selection. We evaluate variants for 41 human traits using data from the NHGRI-EBI GWAS Catalog, as well as data from other three studies. Our results show that variants involving a higher degree of pleiotropy tend to be more common, have larger mean effect sizes, and contribute more to heritability than variants with a lower degree of pleiotropy. This is consistent with the fact that variants of large effect and frequency are more likely detected by GWAS. Using data from four different studies, we also show that more pleiotropic variants are enriched in genome regions with stronger background selection than less pleiotropic variants, suggesting that highly pleiotropic variants are subjected to strong purifying selection. From the above results, we hypothesized that a number of highly pleiotropic variants of low effect/frequency may pass undetected by GWAS.Ministerio de Ciencia, Innovación y Universidades | Ref. FPU18/04642Agencia Estatal de Investigación | Ref. PID2020-114426GB-C21Xunta de Galicia | Ref. ED431C 2020-0

Genetic purging in captive endangered ungulates with extremely low effective population sizes

Inbreeding threatens the survival of small populations by producing inbreeding depression, but also exposes recessive deleterious effects in homozygosis allowing for genetic purging. Using inbreeding-purging theory, we analyze early survival in four pedigreed captive breeding programs of endangered ungulates where population growth was prioritized so that most adult females were allowed to contribute offspring according to their fitness. We find evidence that purging can substantially reduce inbreeding depression in Gazella cuvieri (with effective population size Ne = 14) and Nanger dama (Ne = 11). No purging is detected in Ammotragus lervia (Ne = 4), in agreement with the notion that drift overcomes purging under fast inbreeding, nor in G. dorcas (Ne = 39) where, due to the larger population size, purging is slower and detection is expected to require more generations. Thus, although smaller populations are always expected to show smaller fitness (as well as less adaptive potential) than larger ones due to higher homozygosis and deleterious fixation, our results show that a substantial fraction of their inbreeding load and inbreeding depression can be purged when breeding contributions are governed by natural selection. Since management strategies intended to maximize the ratio from the effective to the actual population size tend to reduce purging, the search for a compromise between these strategies and purging could be beneficial in the long term. This could be achieved either by allowing some level of random mating and some role of natural selection in determining breeding contributions, or by undertaking reintroductions into the wild at the earliest opportunity

Long-term exhaustion of the inbreeding load in Drosophila melanogaster

Inbreeding depression, the decline in fitness of inbred individuals, is a ubiquitous phenomenon of great relevance in evolutionary biology and in the fields of animal and plant breeding and conservation. Inbreeding depression is due to the expression of recessive deleterious alleles that are concealed in heterozygous state in noninbred individuals, the so-called inbreeding load. Genetic purging reduces inbreeding depression by removing these alleles when expressed in homozygosis due to inbreeding. It is generally thought that fast inbreeding (such as that generated by full-sib mating lines) removes only highly deleterious recessive alleles, while slow inbreeding can also remove mildly deleterious ones. However, a question remains regarding which proportion of the inbreeding load can be removed by purging under slow inbreeding in moderately large populations. We report results of two long-term slow inbreeding Drosophila experiments (125–234 generations), each using a large population and a number of derived lines with effective sizes about 1000 and 50, respectively. The inbreeding load was virtually exhausted after more than one hundred generations in large populations and between a few tens and over one hundred generations in the lines. This result is not expected from genetic drift alone, and is in agreement with the theoretical purging predictions. Computer simulations suggest that these results are consistent with a model of relatively few deleterious mutations of large homozygous effects and partially recessive gene actionAgencia Estatal de Investigación (AEI) | Ref. PGC2018-095810-B-I00Agencia Estatal de Investigación (AEI) | Ref. PID2020-114426GB-C21Xunta de Galicia | Ref. ED431C 2020-0

GWEHS: A Genome-Wide Effect Sizes and Heritability Screener

During the last decade, there has been a huge development of Genome-Wide Association Studies (GWAS), and thousands of loci associated to complex traits have been detected. These efforts have led to the creation of public databases of GWAS results, making a huge source of information available on the genetic background of many diverse traits. Here we present GWEHS (Genome-Wide Effect size and Heritability Screener), an open-source online application to screen loci associated to human complex traits and diseases from the NHGRI-EBI GWAS Catalog. This application provides a way to explore the distribution of effect sizes of loci affecting these traits, as well as their contribution to heritability. Furthermore, it allows for making predictions on the change in the expected mean effect size, as well as in the heritability as new loci are found. The application enables inferences on whether the additive contribution of loci expected to be discovered in the future will be able to explain the estimates of familial heritability for the different traits. We illustrate the use of this tool, compare some of the results obtained with those from a previous meta-analysis, and discuss its uses and limitations

Predictive Model and Software for Inbreeding-Purging Analysis of Pedigreed Populations

The inbreeding depression of fitness traits can be a major threat to the survival of populations experiencing inbreeding. However, its accurate prediction requires taking into account the genetic purging induced by inbreeding, which can be achieved using a “purged inbreeding coefficient”. We have developed a method to compute purged inbreeding at the individual level in pedigreed populations with overlapping generations. Furthermore, we derive the inbreeding depression slope for individual logarithmic fitness, which is larger than that for the logarithm of the population fitness average. In addition, we provide a new software, PURGd, based on these theoretical results that allows analyzing pedigree data to detect purging, and to estimate the purging coefficient, which is the parameter necessary to predict the joint consequences of inbreeding and purging. The software also calculates the purged inbreeding coefficient for each individual, as well as standard and ancestral inbreeding. Analysis of simulation data show that this software produces reasonably accurate estimates for the inbreeding depression rate and for the purging coefficient that are useful for predictive purposes

Data from: Estimation of genetic purging under competitive conditions

Inbreeding depression for fitness traits is a key issue in evolutionary biology and conservation genetics. The magnitude of inbreeding depression, though, may critically depend on the efficiency of genetic purging, the elimination or recessive deleterious mutations by natural selection after they are exposed by inbreeding. However, the detection and quantification of genetic purging for nonlethal mutations is a rather difficult task. Here, we present two comprehensive sets of experiments with Drosophila aimed at detecting genetic purging in competitive conditions and quantifying its magnitude. We obtain, for the first time in competitive conditions, an estimate for the predictive parameter, the purging coefficient (d), that quantifies the magnitude of genetic purging, either against overall inbreeding depression (d ≈ 0.3), or against the component ascribed to nonlethal alleles (dNL ≈ 0.2). We find that competitive fitness declines at a high rate when inbreeding increases in the absence of purging. However, in moderate size populations under competitive conditions, inbreeding depression need not be too dramatic in the medium to short term, as the efficiency of purging is also very high. Furthermore, we find that purging occurred under competitive conditions also reduced the inbreeding depression that is expressed in the absence of competition

Estimation of genetic purging under competitive conditions

Inbreeding depression for fitness traits is a key issue in evolutionary biology and conservation genetics. The magnitude ofinbreeding depression, though, may critically depend on the efficiency of genetic purging, the elimination or recessive deleteriousmutations by natural selection after they are exposed by inbreeding. However, the detection and quantification of genetic purgingfor nonlethal mutations is a rather difficult task. Here, we present two comprehensive sets of experiments with Drosophila aimedat detecting genetic purging in competitive conditions and quantifying its magnitude. We obtain, for the first time in competitiveconditions, an estimate for the predictive parameter, the purging coefficient (d), that quantifies the magnitude of genetic purging,either against overall inbreeding depression (d 0.3), or against the component ascribed to nonlethal alleles (dNL 0.2). We findthat competitive fitness declines at a high rate when inbreeding increases in the absence of purging. However, in moderate sizepopulations under competitive conditions, inbreeding depression need not be too dramatic in the medium to short term, as theefficiency of purging is also very high. Furthermore, we find that purging occurred under competitive conditions also reduced theinbreeding depression that is expressed in the absence of competition