IN THIS ISSUEOFFICIAL JOURNAL

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� Deciphering the cis-Regulatory Land-scape of SOX9 Implicated in CraniofacialDevelopment and Isolated Pierre RobinSequence

Human genetic disorders are most often caused by variants in thecoding region of a disease gene. However, the correct spatiotemporalexpression of most developmental genes is encoded in cis-regulatoryelements (CREs) in the non-coding part of our genome. With theexplosion of knowledge and publicly available sequencing data, itis expected that the number of studies exploring the non-codingportion of the genome will steeply increase. This shift is especiallyrelevant for developmental disorders that are often caused by defectsin transcription factor genes and that have been instrumental inrevealing a variety of non-coding defects, some of which involveCREs located far away from their target genes.

The SOX9 locus has been exemplary for the discovery of myriaddefects outside the SOX9 transcription unit in isolated endopheno-types differing from the full phenotypic spectrum caused by SOX9coding mutations. Indeed, translocations, copy number variationsand subtle sequence variations of non-coding CREs were foundin isolated Pierre Robin sequence (PRS), campomelic dysplasia(CD), disorders of sex development (DSD) and recently congenitalheart defects (CHD), whereas coding SOX9 mutations lead to syn-dromic CD with PRS and DSD. These phenotypic differences em-phasize the tissue-specificity of CREs of developmental genes suchas SOX9.

In this issue, Gordon et al. (Hum Mutat 35:1011–1020, 2014)identified two novel upstream deletions in a series of nineteen PRSpatients: a deletion of 280 kb overlapping with previously identifiedupstream deletions, uncovering new candidate craniofacial CREscontaining four conserved non-genic elements (CNEs); and a smalldeletion of 6 kb containing one single CNE. Convincing evidencefor their functional consequences was provided by integrated epige-netic studies (ChIP-Seq for p300 or H3K27ac in mouse embryoniccraniofacial and palatal tissue) and in vivo reporter assays in mouseand zebrafish. This study adds to the growing body of research in thenon-coding genome, which represents an emerging field in humangenetics.

Elfride De Baere

Ghent University and Ghent University Hospital,Belgium

DOI: 10.1002/humu.22411

� What Identity Crisis? Rapidly Mutat-ing Y-STRs Facilitate Differentiation ofMales

Short tandem repeats (STRs) on the Y-chromosome are widely ap-plied to the determination of patrilineal relationships. In forensics,Y-STRs are particularly beneficial in the investigation of sexual as-sault cases, where the female victim’s vaginal epithelial cell DNA istypically present in large excess over the male perpetrator’s spermand epithelial cell DNA in vaginal swab material. A number of com-mercial Y-STR kits are available, including the AmpFlSTR R© Yfiler R©

PCR amplification kit (Life Technologies), which incorporates 17“core” Y-STR markers into a single multiplex analysis system. De-spite their ability to discriminate two unrelated males in most cases,the core Y-STR markers are not suited for differentiation of relatedmales, who are likely to share the same core Y-STR haplotype.

An important step towards completely differentiating even closelyrelated males employing Y-STRs was made in 2010, when the groupof Manfred Kayser in Rotterdam identified 13 Y-STR markers, sub-sequently termed rapidly mutating (RM) Y-STRs, whose medianmutation rate was 6.5-fold higher than that estimated for the Yfiler R©

STRs (Ballantyne et al., Am J Hum Genet 87: 341–353, 2010). The RMY-STR set succeeded in distinguishing 70% of the 20 investigatedfather-son pairs, while the Yfiler R© set differentiated none. Further,with the RM Y-STRs only three haplotypes were shared among 8 of604 worldwide HGDP-CEPH males, compared to 33 Yfiler R© hap-lotypes shared among 85 males (Ballantyne et al., Forensic Sci IntGenet 6:208–218, 2012).

In this issue, 123 international investigators led by Prof. Kaysergenotyped 12,272 unrelated males from 111 worldwide populationsfor the 13 RM Y-STRs (Ballantyne et al., Hum Mutat 35:1021–1032,2014). Strikingly, >99% of the unrelated males were completely in-dividualized with virtually absent (0.05%) or rare (0.8%) haplotypesharing between and within populations, respectively. Haplotypediversity and average percentage of allelic differences amounted to0.999997 and 81%, while the respective values for the Yfiler R© setwere 0.99995 and 65%. Further, the RM Y-STR set differentiated26.9% of the 2,378 additionally investigated father-son pairs, versus4.5% for the Yfiler R© set. The near-complete male individualiza-tion provided by the 13 RM Y-STR set will reduce the probabilityof adventitious matches or male relative involvement in forensiccasework where a non-exclusion is observed with the current coreY-STRs.

Peter J. Oefner

Universitat Regensburg, Germany

DOI: 10.1002/humu.22412

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