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.

Keywords: animal breeding; artificial selection; balancing selection; loss-of-function; overdominance.

FIGURE 1

Schematic overview of the MSTN stop gained variant in pigs (Matika et al., 2019). The stop codon affects the third exon of the MSTN gene, leading to a premature stop codon and a loss of function of the myostatin protein. Heterozygotes exhibit the double muscling phenotypes, while homozygotes suffer from leg weakness.

FIGURE 2

Schematic overview of the polledness trait in Soay sheep (Johnston et al., 2013; Wiedemar and Drögemüller, 2015). The polledness phenotype is associated with a EEF1A1-like insertion in the 3′UTR of the RXFP2 gene. The insertion potentially leads to RXFP2 post transcriptional regulation by binding EEF1A1 transcripts (caused by double stranded RNA degradation). Homozygous wildtype sheep have horns and higher reproductive success but lower survival, whereas homozygous ins/ins sheep exhibit lower reproductive success but higher survival. Heterozygotes exhibit the highest overall fitness underlying balancing selection.

FIGURE 3

Examples of (A) Mummified piglet resulting from a large deletion in pigs, figure from (Derks et al., 2018). (B) Ovine hereditary chondrodysplasia, also known as the Spider Lamb Syndrome, figure from (Thompson et al., 2008) (C) Lethal white foal syndrome, figure from (Ayala-Valdovinos et al., 2016) (D) White heifer disease, figure from (de Meuter, 2010).

FIGURE 4

Population genetic simulations for deleterious alleles with Ne = 100. (A) Frequency simulation of a deleterious allele at starting frequency 1%. The fitness of the homozygous BB genotype = 0, with equal fitness for the AB and AA genotype (fitness = 1). Figure shows that the allele is lost in the vast majority of the populations after 50 generations. The maximum frequency reached by drift is approximately 10%. (B) Frequency simulation of a deleterious allele with the fitness of the homozygous BB genotype = 0, and the AB genotype has a 10% fitness advantage over the homozygous AA genotype (AB = 1, AA = 0.9). Figure shows that the allele is lost in about one third of the populations after 50 generations. In two third of the populations the allele remains at a relatively stable equilibrium between 5–15% allele frequency.

FIGURE 5

Frequency of the MC4R - Asn298 allele in four commercial pig breeds from Topigs Norsvin. The Asn298 allele is associated with more fat, higher feed consumption and faster growth, while the Asp298 allele is associated with less backfat, slower growth, and lower feed intake (Kim et al., 2000).