A Functional Variable Number of Tandem Repeats is Located at the 5′ Flanking Region of the Human Secretin Gene Plays a Downregulatory Role in Expression

The human DEAD-box Y (DBY) RNA helicase (aka DDX3Y) gene is thought to be the major azoospermia factor a (AZFa) gene in proximal Yq11. Men with its deletion display no somatic pathologies, but suffer from complete absence of germ cells. Accordingly, DDX3Y protein is expressed only in the germline in spermatogonia, although the transcripts were found in many tissues. Here, we show the complex transcriptional control of a testis-specific DDX3Y transcript class with initiation at different sites upstream of the gene’s open reading frame (5′Untranslated Region; UTR) and with polyadenylation in their proximal 3′UTR. The most distal transcriptional start site (TSS; ∼1 kb upstream) was mapped in MSY2, a Y-specific minisatellite. As this testis-specific 5′UTR was subsequently processed by three alternative splicing events, it has been tentatively designated ‘exon-T’(estis). The MSY2 sequence unit was also found upstream of the mouse Ddx3y gene. However, only after its tandem amplification on the Y chromosome of Platyrrhini (new world monkeys) and Catarrhini (old world monkeys) did MSY2 become part of a novel distal promoter for DDX3Y expression in testis tissue and provides a second transcriptional start site (T-TSS-II) in Catarrhini. We therefore suggest that the development of a novel distal DDX3Y promoter in primates, which is activated only in testis tissue, is probably part of the gene’s germline translation control.

show abstract

“…Short tandem repeats contain an inherent ‘enhancer’ quality to control the transcriptional efficiency of the downstream gene (Lee et al. , 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Short tandem repeats contain an inherent 'enhancer' quality to control the transcriptional efficiency of the downstream gene (Lee et al, 2008). Multiple examples are therefore known where variation in sequence or copy number of a minisatellite located upstream of a gene can cause significant human pathologies (e.g.…”

Section: Discussionmentioning

confidence: 99%

Complex transcriptional control of the AZFa gene DDX3Y in human testis

Rauschendorf¹,

Zimmer²,

Hanstein³

et al. 2011

International Journal of Andrology

View full text Add to dashboard Cite

show abstract

“…Tandem repeat instability has also been implicated in a variety of other diseases including coronary artery disease, polycystic ovary disease, ADHD, type II diabetes and obesity (3–7). It is also a common source of human genetic variation that may affect gene expression but is not obviously pathological (8,9). …”

Section: Introductionmentioning

confidence: 99%

ATM and ATR protect the genome against two different types of tandem repeat instability in Fragile X premutation mice

Entezam

Usdin

2009

Nucleic Acids Research

View full text Add to dashboard Cite

Expansion of a tandem repeat tract is responsible for the Repeat Expansion diseases, a group of more than 20 human genetic disorders that includes those like Fragile X (FX) syndrome that result from repeat expansion in the FMR1 gene. We have previously shown that the ATM and Rad3-related (ATR) checkpoint kinase protects the genome against one type of repeat expansion in a FX premutation mouse model. By crossing the FX premutation mice to Ataxia Telangiectasia-Mutated (Atm) mutant mice, we show here that ATM also prevents repeat expansion. However, our data suggest that the ATM-sensitive mechanism is different from the ATR-sensitive one. Specifically, the effect of the ATM deficiency is more marked when the premutation allele is paternally transmitted and expansions occur more frequently in male offspring regardless of the Atm genotype of the offspring. The gender effect is most consistent with a repair event occurring in the early embryo that is more efficient in females, perhaps as a result of the action of an X-linked DNA repair gene. Our data thus support the hypothesis that two different mechanisms of FX repeat expansion exist, an ATR-sensitive mechanism seen on maternal transmission and an ATM-sensitive mechanism that shows a male expansion bias.

show abstract

“…These results are not surprising given that a relationship between the number of regulatory repeat elements and transcript copy number has been well described for other genes (Sgourou et al 2004;Lee et al 2008;Akhtar et al 2009). A similar correlation between Sub2 transcript copy number and microsatellite copy number in the 3 0 UTR appears to be present, however, all copy-number variations were not represented among the isolates studied and thus the association cannot be confirmed.…”

Section: Non-synonymous Snpsmentioning

confidence: 72%