Review: Balancing Selection for Deleterious Alleles in Livestock

Abstract

Harmful alleles can be under balancing selection due to an interplay of artificial selection for the variant in heterozygotes and purifying selection against the variant in homozygotes. These pleiotropic variants can remain at moderate to high frequency expressing an advantage for favorable traits in heterozygotes, while harmful in homozygotes. The impact on the population and selection strength depends on the consequence of the variant both in heterozygotes and homozygotes. The deleterious phenotype expressed in homozygotes can range from early lethality to a slightly lower fitness in the population. In this review, we explore a range of causative variants under balancing selection including loss-of-function variation (i.e., frameshift, stop-gained variants) and regulatory variation (affecting gene expression). We report that harmful alleles often affect orthologous genes in different species, often influencing analogous traits. The recent discoveries are mainly driven by the increasing genomic and phenotypic resources in livestock populations. However, the low frequency and sometimes subtle effects in homozygotes prevent accurate mapping of such pleiotropic variants, which requires novel strategies to discover. After discovery, the selection strategy for deleterious variants under balancing selection is under debate, as variants can contribute to the heterosis effect in crossbred animals in various livestock species, compensating for the loss in purebred animals. Nevertheless, gene-assisted selection is a useful tool to decrease the frequency of the harmful allele in the population, if desired. Together, this review marks various deleterious variants under balancing selection and describing the functional consequences at the molecular, phenotypic, and population level, providing a resource for further study.

Homozygous haplotype deficiency in Manech Tête Rousse dairy sheep revealed a nonsense variant inMMUTgene affecting newborn lamb viability

“…It is thus unlikely that selective advantage explains the observed DHH frequencies, or the rapid increase in MTRDHH3 frequency between 2017 and 2018. However, many examples of balancing selection for deleterious alleles have been described in livestock [52]. For example in sheep, a missense variant in FGFR3 was associated with enhanced skeletal growth and meat yield when heterozygous while it induced chondrodysplasia (spider lamb syndrome) when homozygous (OMIA 001703-9940) [53].…”

Genetics of the phenotypic evolution in sheep: a molecular look at diversity-driving genes

“…It was shown that horned individuals were homozygous for the absence of the insertion, whereas polled individuals were homozygous for its presence. It has been speculated that when the EEF1A1-like insertion is present, EEF1A1 transcripts bind to the 3′-UTR of the RXFP2 mRNA, leading to post-transcriptional downregulation [ 56 , 57 ]. In Bündner Oberländer sheep with both polled and horned phenotypes, horned individuals were homozygous for the absence of the insertion; however, two polled individuals were found to be heterozygous for the insertion.…”

Identification of lethal recessive genetic variants in Holstein cattle

“…Usually, these types of harmful alleles are eliminated from the population by selection, which can be effective for dominant harmful alleles that reduce the fitness of heterozygous animals. Nevertheless, due to the low frequency, recessive harmful alleles are usually masked from natural selection by a dominant harmless allele and therefore easily transmitted to the next generation [4]. This effect is called balancing selection.…”