Identification and characterization of novel rapidly mutating Y‐chromosomal short tandem repeat markers

Abstract

Short tandem repeat polymorphisms on the male‐specific part of the human Y‐chromosome (Y‐STRs) are valuable tools in many areas of human genetics. Although their paternal inheritance and moderate mutation rate (~10−3 mutations per marker per meiosis) allow detecting paternal relationships, they typically fail to separate male relatives. Previously, we identified 13 Y‐STR markers with untypically high mutation rates (>10−2), termed rapidly mutating (RM) Y‐STRs, and showed that they improved male relative differentiation over standard Y‐STRs. By applying a newly developed in silico search approach to the Y‐chromosome reference sequence, we identified 27 novel RM Y‐STR candidates. Genotyping them in 1,616 DNA‐confirmed father–son pairs for mutation rate estimation empirically highlighted 12 novel RM Y‐STRs. Their capacity to differentiate males related by 1, 2, and 3 meioses was 27%, 47%, and 61%, respectively, while for all 25 currently known RM Y‐STRs, it was 44%, 69%, and 83%. Of the 647 Y‐STR mutations observed in total, almost all were single repeat changes, repeat gains, and losses were well balanced; allele length and fathers' age were positively correlated with mutation rate. We expect these new RM Y‐STRs, together with the previously known ones, to significantly improving male relative differentiation in future human genetic applications.

Next Generation Sequencing of Y-STRs in Father-Son Pairs and Comparison with Traditional Capillary Electrophoresis

“…Thus, for differentiation of father-son pairs, analysing more RM Y-STRs with CE seems to be a much more promising approach than just sequencing the common Y-STRs. Recently, Ralf et al proposed 12 new RM Y-STRs with a mean mutation rate of 2.6 × 10 −2 , demonstrating high discrimination power [34]. We also agree with Huszar et al that applying MPS to RM Y-STRs is expected to increase discriminatory power as allele diversity increases.…”

“…Mutations were observed at all types of markers, including simple and complex repeat structures and trimeric to hexameric repeat structures. Our results suggest that tetranucleotide repeats are more prone to mutations than other motifs [32][33][34], mutation events are mostly restricted to the LUS of a compound/complex STR marker [31,32,34,35], and the LUS length correlates with the mutability of an STR marker [32][33][34][36][37][38]. Unsurprisingly, when looking at the sequence variants between unrelated males, we found that the observed length variance is mainly explained by changes in the repetitive structure of a Y-STR.…”

The Y‐STR landscape of coastal southeastern Han: Forensic characteristics, haplotype analyses, mutation rates, and population genetics

“…Arwin Ralf et al. [11] applied a newly developed in silico search approach to the Y‐chromosome reference sequence, and highlighted 12 novel RM Y‐STRs in Europe. It is one of the efficient ways to strengthen the capacity of RM Y‐STR system for differentiating relative or unrelated males.…”

“…In general, forensic DNA analysis seeks individual identification [11]. Male relative differentiation using Y‐chromosome markers has been achieved by rapidly mutating Y‐STRs, which are termed RM Y‐STRs [12,13], with mutation rates ( μ ) > 10 –2 .…”

“…However, the identified set of 13 RM Y‐STR markers provides limitations for male relative differentiation, particularly regarding close patrilineal relatives and different mutation rates for the same Y‐STR marker in different populations, which limits applications in forensic genetics and genetic genealogy [22]. Hence, in order to strengthen the capacity of RM Y‐STR system for differentiating relative or unrelated males, there are two ways to improve the RM Y‐STR system, ( a) find novel RM Y‐STR markers to expand the RM Y‐STRs pool [11], and ( b) validate and evaluate currently known Y‐STRs as new candidate RM Y‐STR markers in different populations for regional individual identification. Depend on different mutation rates of Y‐STR markers, the strategy of forensic DNA analysis, slowly mutating Y‐STRs (SM Y‐STRs, μ < 10 –3 ) [13] for familial searching and RM Y‐STRs for individual identification, is extremely feasible with the establishment of forensic Y‐STR databases and the accumulation of Y‐STR profiles.…”