MYADM gene family tandem duplication strongly linked to sheep erythrocyte potassium concentration

The concentration of intracellular potassium in erythrocytes varies significantly among domestic sheep, categorized as low (LK) or high (HK) potassium phenotypes. These differences are linked to varying rates of potassium chloride co-transport (KCC), a crucial mechanism for cellular volume regulation and ion homeostasis. While this trait is inherited as a single locus, the specific genetic variants responsible have remained elusive. Understanding the genetic basis of KCC regulation is vital, as KCCs, particularly KCC3, are implicated in human conditions like hypertension and neurological disorders, highlighting a critical gap in our knowledge of their regulatory mechanisms.

Researchers conducted a genome-wide association study (GWAS) in domestic sheep to identify genetic variants associated with erythrocyte intracellular potassium concentration. Following the initial GWAS, fine mapping was performed in an expanded sheep population to pinpoint specific genes within the identified locus. To explore potential molecular interactions, Alphafold3 protein models were utilized to predict how human MYADM protein might interact with KCC3 to influence its activity. The study aimed to link genetic variations in the MYADM family to the observed physiological differences in erythrocyte potassium levels.

The genome-wide association study identified a large, artiodactyl-specific tandem duplication of the MYADM gene family locus as highly associated with erythrocyte intracellular potassium concentration, achieving a remarkable significance of P = 1.1 × 10^-63. This expanded MYADMF locus contained 37 genes in sheep, 33 in goats, 52 in cattle, and 15 in domestic swine, but no comparable expansion in horses. Fine mapping in an expanded sheep population further refined this association, showing maximal linkage to erythrocyte potassium with P < 10^-99 for specific genes: MYADMF15A1, MYADMF1G1, MYADMF1H1, MYADMF3A1, MYADMF1B3, and MYADMF13C1. Prior data indicated higher potassium chloride co-transport in sheep LK erythrocytes compared to HK erythrocytes. The current findings, for the first time, implicate one or more MYADMF genes in the regulation of potassium chloride co-transport. Given fewer MYADM genes in humans, a simpler interaction was hypothesized with the namesake MYADM, which has been linked to human hypertension.

Alphafold3 protein models suggest that human MYADM directly interacts with KCC3 to stabilize its N-terminal regulatory peptide in an inhibitory position. This interaction provides a plausible mechanism for how divergent alleles, such as MYADMF1G1 and MYADMF1B3 (or MYADMF15A1), could cause the low potassium phenotype by affecting KCC3 function.