Mysteries in our genome

Journal of Genetics (2023)102:1 https://doi.org/10.1007/s12041-022-01392-9 Ó Indian Academy of Sciences (0123456789().,-volV) (0123456789().,-volV) EDITORIAL Mysteries in our genome . ; accepted 14 September 2022 DURGADAS P. KASBEKAR The human, rat, and mouse genomes share about 500 segments, each more than 200-bp long, of perfect (100%) DNA sequence identity. These ultraconserved elements (UCEs) have not tolerated even a single base-pair change since we shared a last common ancestor with rodents about 80 million years ago. Nearly all of the UCEs are also highly conserved (more than 95% identity) in the chicken and dog genomes, and many are also significantly conserved in fish. We have no idea what selective constraints have maintained the UCEs. At the other end of the DNA sequence conservation spectrum, are the rapidly mutating short tandem repeats on the Y chromosome (RM Y-STRs). These elements mutate rapidly enough such that even father–son pairs can show differences (Am. J. Hum. Genet. 87, 341–353, 2010). We do not know why RM Y-STR sequences are so much more mutable than the STRs routinely used for forensic studies. The UCEs and RM Y-STRs are two contrasting mysteries in our genome. The first report of a UCE came from Rakesh Mishra and colleagues in the Centre for Cellular and Molecular Biology (CCMB) (https://genomebiology.biomedcentral.com/articles/10.1186/gb-2003-4-4-p2). And an early report on RM Y-STRs (Hum. Mutat. 35, 1021–1032, 2014) included J. Nagaraju and S. P. R. Prasad of the Centre for DNA Fingerprinting and Diagnostics (CDFD) among its authors. (Sadly, Nagaraju’s authorship was posthumous because of his untimely death, at age 58, on 31 December 2012. Two years earlier, Nagaraju and Giuseppe Saccone edited a special issue on Sex Determination in Insects in this Journal.) My association with CCMB and CDFD gave me ringside views of UCE and RM Y-STR discovery. Other researchers found, most unexpectedly, that mice lacking individual UCEs were viable and had no obvious phenotype (PLoS Biol. 5, e234, 2007). Short conserved sequences have often been proposed to serve as enhancers of gene expression. Might UCEs be exceptionally long enhancers? A subset of mouse UCEs indeed showed enhancer activity. But this function also was not significantly perturbed in mice bearing mutated versions (Nat. Genet. 53, 521–528, 2021). So ultraconservation must have some other explanation. What conserved biological function might require a unique 200-bp sequence? It was speculated that UCEs might be part of some chromosome counting mechanism, but there was no experimental evidence for this. Analysis of the genome of thousands of individuals even identified rare sequence polymorphisms in UCEs, which showed that they were not mutational cold spots. The suggestion that in recent human evolution UCEs could accumulate polymorphisms because they lost an earlier crucial function which was not very convincing. RM Y-STRs have been used to distinguish between related males. To give just one example, DNA examiners in CDFD determined the autosomal and Y STR profiles from a bloodstain recovered from a crime scene. The police then found an individual with a very similar Y STR profile, except that he carried a different allele at the DYS576 RM Y-STR locus. The CDFD examiners advised the police to search among this individual’s paternal relatives, but to focus on those carrying the DYS576 allele found at the crime scene. The investigators quickly zeroed into a paternal cousin whose DNA profile fully matched that of the bloodstain. This established that the cousin was present at the crime scene. So RM Y-STRs undoubtedly have uses. But what explains their exceptionally high mutability? No paper has as yet addressed this question. We have still to make sense of UCEs and RM Y-STRs ‘in the light of evolution’. It is reassuring to know much remains to be discovered. E-mail: . Durgadas P. Kasbekar Editor-in-Chief Journal of Genetics  (...truncated)