Genomic complexity of the Y-STR DYS19: inversions, deletions and founder lineages carrying duplications

Abstract

The Y-STR DYS19 is firmly established in the repertoire of Y-chromosomal markers used in forensic analysis yet is poorly understood at the molecular level, lying in a complex genomic environment and exhibiting null alleles, as well as duplications and occasional triplications in population samples. Here, we analyse three null alleles and 51 duplications and show that DYS19 can also be involved in inversion events, so that even its location within the short arm of the Y chromosome is uncertain. Deletion mapping in the three chromosomes carrying null alleles shows that their deletions are less than approximately 300 kb in size. Haplotypic analysis with binary markers shows that they belong to three different haplogroups and so represent independent events. In contrast, a collection of 51 DYS19 duplication chromosomes belong to only four haplogroups: two are singletons and may represent somatic mutation in lymphoblastoid cell lines, but two, in haplogroups G and C3c, represent founder lineages that have spread widely in Central Europe/West Asia and East Asia, respectively. Consideration of candidate mechanisms underlying both deletions and duplications provides no evidence for the involvement of non-allelic homologous recombination, and they are likely to represent sporadic events with low mutation rates. Understanding the basis and population distribution of these DYS19 alleles will aid in the utilisation and interpretation of profiles that contain them.

Fig. 1

Complex genomic environment of DYS19 and putative mechanisms for inversions, deletions and duplications. a Reference sequence organisation around DYS19, showing position of the Y-STR on an idiogram of the Y chromosome (with genome position of start of the marker given according to build 36.1 of the reference assembly), and below, a schematic view of the region around DYS19 and its paralogues (pDYS19) on Yq. Arrows indicate inverted repeats (IR3 elements) or large repeat units in the region proximal to AZFc [42]. STSs and other markers used in mapping are shown below. b Structure of Yp following IR3-mediated inversion, with breakpoints indicated by dotted lines and mapping of presence (+) or absence (−) of markers in XX male WA48. The horizontal dotted line indicates the region of uncertainty of the breakpoint, resulting from the wide marker spacing. c Alignment of the IR3 inverted repeats; in the reference sequence organisation, DYS19 lies within the proximal IR3, corresponding to a 3-kb gap in the distal IR3. d Putative mechanism of DYS19 deletion or duplication mediated by unequal exchange (curved grey arrow) between flanking direct partial L1 repeats within the proximal IR3. Small arrows indicate PCR primers used to seek junction PCR products in deletion and duplication chromosomes

Fig. 2

Haplogroups and Y-STR haplotypes of DYS19 deletion and duplication chromosomes. a Binary marker phylogeny of the Y chromosome, with haplogroups (hg) [19] containing DYS19 deletion and duplication chromosomes indicated by coloured circles. b) Weighted median joining network [33] containing the 14-locus (DYS388, DYS389I, DYS389II-I, DYS390, DYS391, DYS392, DYS393, DYS426, DYS437, DYS439, DYS434, DYS435, DYS436 and DYS438) Y-STR haplotypes of 3 deletion and 51 duplication chromosomes. Circles represent haplotypes, with area proportional to frequency and coloured according to haplogroup as in a. Nodes used as roots in TMRCA estimations are indicated by asterisks