Strongly deleterious mutations are a primary determinant of extinction risk due to inbreeding depression

Abstract

Human-driven habitat fragmentation and loss have led to a proliferation of small and isolated plant and animal populations with high risk of extinction. One of the main threats to extinction in these populations is inbreeding depression, which is primarily caused by recessive deleterious mutations becoming homozygous due to inbreeding. The typical approach for managing these populations is to maintain high genetic diversity, increasingly by translocating individuals from large populations to initiate a “genetic rescue.” However, the limitations of this approach have recently been highlighted by the demise of the gray wolf population on Isle Royale, which declined to the brink of extinction soon after the arrival of a migrant from the large mainland wolf population. Here, we use a novel population genetic simulation framework to investigate the role of genetic diversity, deleterious variation, and demographic history in mediating extinction risk due to inbreeding depression in small populations. We show that, under realistic models of dominance, large populations harbor high levels of recessive strongly deleterious variation due to these mutations being hidden from selection in the heterozygous state. As a result, when large populations contract, they experience a substantially elevated risk of extinction after these strongly deleterious mutations are exposed by inbreeding. Moreover, we demonstrate that, although genetic rescue is broadly effective as a means to reduce extinction risk, its effectiveness can be greatly increased by drawing migrants from small or moderate-sized source populations rather than large source populations due to smaller populations harboring lower levels of recessive strongly deleterious variation. Our findings challenge the traditional conservation paradigm that focuses on maximizing genetic diversity in small populations in favor of a view that emphasizes minimizing strongly deleterious variation. These insights have important implications for managing small and isolated populations in the increasingly fragmented landscape of the Anthropocene.

Mutation load decreases with haplotype age in wild Soay sheep

“…CC-BY-NC-ND 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is The copyright holder for this preprint this version posted March 5, 2021. ; https://doi.org/10.1101/2021.03.04.433700 doi: bioRxiv preprint 14 populations, which facilitates purging of mutations with large fitness effects despite a relatively low efficiency of selection due to drift (Hedrick & Garcia-Dorado, 2016;Kyriazis, Wayne, & Lohmueller, 2021). Yet, inbreeding depression is strong in Soay sheep, and highly inbred individuals are very unlikely to survive their first winter (Figure 1b, Stoffel et al, 2020).…”

“…At the haplotype level, we showed that purifying selection constantly removes deleterious variation, causing a difference in the mutation load of IBD haplotypes with different coalescent times. Strongly deleterious mutations are purged relatively quickly, probably because they frequently occur as homozygotes in small populations, which facilitates purging of mutations with large fitness effects despite a relatively low efficiency of selection due to drift (Hedrick & Garcia-Dorado, 2016;Kyriazis, Wayne, & Lohmueller, 2021). Yet, inbreeding depression is strong in Soay sheep, and highly inbred individuals are very unlikely to survive their first winter (Figure 1b, Stoffel et al, 2020).…”

Low Persistence of Genetic Rescue Across Generations in the Arctic Fox (Vulpes lagopus)

“…In absence of maternal effects of inbreeding ( Frankham 2015 ), genetic rescue is predicted to be most profound in immigrant F1 and level off in more distant descendants. It is however also possible that gene flow into an extremely small population can introduce recessive deleterious alleles that become expressed in immigrant F2 and F3 ( Whiteley et al 2014 ; Hedrick and Garcia-Dorado 2016 ; Bell et al 2019 ; Kyriazis et al 2021 , but see Ralls et al 2020 ). Such consequences are however only expected when inbreeding levels in the recipient population are already high, population size low and gene flow occurs as one single event ( Ralls et al 2020 ).…”

Genomic signatures of inbreeding and genetic load in a threatened rattlesnake

“…Second, consideration of the potential effects of long-term purging on mutational load have led to suggestions that conventional guidelines for conducting genetic rescue of small inbred populations of threatened species need to be reconsidered (Kyriazis et al, 2020;van der Valk et al, 2019; but see Ralls et al, 2020). Specifically, Kyriazis et al (2020) argue that the typical approach for managing these populations is to maintain high genetic diversity through the transfer of individuals from large genetically diverse populations but that this carries a risk of introducing large numbers of deleterious mutations that can be exposed by inbreeding. Our empirical results show that, in fact, there is an inverse relationship between levels of mutational load and effective size among S. catenatus populations or that large potential donor populations have fewer not more potential deleterious mutations present.…”

“…Thus, the type and level of genetic load present in a given population reflects a balance of the relative magnitudes of these distinct processes (inbreeding versus reduced selection due to drift) with opposite effects on mutation frequencies. As a result, assessing levels of inbreeding, effective population size, and levels of genetic load are an important goal of empirical studies that seek to assess the genetic risks impacting long term viability of threatened species (Mathur & DeWoody, 2021) and for assessing the appropriateness of specific management activities such as genetic rescue for mitigating these risks (Kyriazis, Wayne, & Lohmueller, 2020; but see Ralls, Sunnucks, Lacy, & Frankham, 2020).…”