Eyes wide open: the (mis)use of combined power of discrimination for X-linked short tandem repeats

Abstract

In the field of Genetic Epidemiology it is well established that ignoring interallelic multipoint gametic disequilibrium (GD) introduces false-positive evidence of linkage for sibpair (kinship) analysis, especially in cases of sample deficiencies [1]. In the field of Forensic Genetics this proven concept is, in stark contrast, largely trivialized or ignored. There is an alarming accrual of forensic reports (Online Resource 1) announcing population data on short tandem repeats loci mapping on X chromosome (X-STRs) in which the product rule is applied to syntenic loci (i.e., being located on the same chromosome whether or not there is demonstrable genetic linkage between them), mostly ignoring the second law of Mendelian inheritance, and fundamental notions on genetic linkage status. We believe that the issue has been utterly disregarded, and thus it can no longer go unnoticed without opinion. We center our opinion at the most crucial aspect that underlies meaningful calculation of combined power of discrimination (CPD), as it applies to forensic and medical genetics: accurate knowledge about genetic linkage status of X-STRs loci [2]. X chromosome is endowed with distinctive characteristics mainly derived from how it is inherited by male and female offspring. Contrasting to autosomes, and excluding the pseudoautosomal regions present in both X and Y chromosomes, X chromosome recombination only occurs in females, so every existing X chromosome has evolved two-thirds of its history in them [3]. Syntenic loci may, in principle, be subjected to GD, which is a multifactorial evolutionary dynamic phenomenon that occurs at normal selection, characterized by significant and intensity-variable non-random associations of alleles at different DNA loci, physically mapped on the same (even though not necessarily) chromosomal DNA molecule [4]. GD is affected by, and therefore it is an indicator of, extreme allele frequencies, allele mutation rate, selection, genetic drift, gene flow, recombination, admixture, and the demographic history of populations [5]. A first conundrum with typing syntenic X-STRs loci is whether, and if so how, to compute the genotype evidence (phased our unphased diplotypes and male haplotypes) in favor of a matching hit (i.e., coinciding profiles) or against it (i.e., allelic exclusion). Solving this riddle will help responding the practical question ‘‘what is the evidential value of an X haplotype?’’ This problem is of considerable lesser extent in relation to the field of YSTRs haplotypes [6], from which important lessons ought to be learned. It helps to keep in mind that matching haplotypes can reflect either ‘‘identity by descend’’ (IBD; i.e., related haplotypes with no intervening mutations) or ‘‘identity by Electronic supplementary material The online version of this article (doi:10.1007/s11033-010-0518-z) contains supplementary material, which is available to authorized users.