Complex Selection on Human Polyadenylation Signals Revealed by Polymorphism and Divergence Data.
Polyadenylation is a step of mRNA processing which is crucial for its expression and stability. The major polyadenylation signal (PAS) represents a nucleotide hexamer that adheres to the AATAAA consensus sequence. Over a half of human genes have multiple cleavage and polyadenylation sites, resulting in a great diversity of transcripts differing in function, stability, and translational activity. Here, we use available whole-genome human polymorphism data together with data on interspecies divergence to study the patterns of selection acting on PAS hexamers. Common variants of PAS hexamers are depleted of single nucleotide polymorphisms (SNPs), and SNPs within PAS hexamers have a reduced derived allele frequency (DAF) and increased conservation, indicating prevalent negative selection; at the same time, the SNPs that "improve" the PAS (i.e., those leading to higher cleavage efficiency) have increased DAF, compared to those that "impair" it. SNPs are rarer at PAS of "unique" polyadenylation sites (one site per gene); among alternative polyadenylation sites, at the distal PAS and at exonic PAS. Similar trends were observed in DAFs and divergence between species of placental mammals. Thus, selection permits PAS mutations mainly at redundant and/or weakly functional PAS. Nevertheless, a fraction of the SNPs at PAS hexamers likely affect gene functions; in particular, some of the observed SNPs are associated with disease.
Centre for Developmental Neurobiology, King's College London, London, United Kingdom Oncogenes Regulation Department, N.N. Blokhin Russian Cancer Research Center, Institute of Carcinogenesis, Moscow, Russia yaroslav.kainov@kcl.ac.uk gbazykin@iitp.ru.
Yaroslav A
YA
Kainov
Oncogenes Regulation Department, N.N. Blokhin Russian Cancer Research Center, Institute of Carcinogenesis, Moscow, Russia Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York.
Vasily N
VN
Aushev
Institute for Information Transmission Problems (Kharkevich Institute) of the Russian Academy of Sciences, Moscow, Russia Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Canada.
Sergey A
SA
Naumenko
Oncogenes Regulation Department, N.N. Blokhin Russian Cancer Research Center, Institute of Carcinogenesis, Moscow, Russia.
Elena M
EM
Tchevkina
Institute for Information Transmission Problems (Kharkevich Institute) of the Russian Academy of Sciences, Moscow, Russia Skolkovo Institute of Science and Technology, Skolkovo, Russia Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Russia Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Russia Pirogov Russian National Research Medical University, Moscow, Russia yaroslav.kainov@kcl.ac.uk gbazykin@iitp.ru.
Georgii A
GA
Bazykin
D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D015894:Genome, Human; D006801:Humans; D026723:Polyadenylation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D039104:RNA 3' Polyadenylation Signals / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*
D012333:RNA, Messenger
1000 genomes; AATAAA; SNP; mRNA processing; polyadenylation