Recent Inserts of Transposable Elements Affect Structure and Functions of Human Genome

Abstract

Transposable elements (TEs) are selfish fragments of DNA able to reproduce themselves into the host genomes. TEs typically occupy ∼40–50% of the mammalian genomes. In our studies, we focus on evolutionary recent TE inserts that appeared in the DNA of human ancestor lineage after divergence with the chimpanzee ancestry, i.e. less than ∼6 million years ago. These human specific elements (hsTEs) represent only a minor fraction of the whole TE cargo of the human genome. hsTEs are represented by the four families called HERV-K(HML-2), L1, Alu and SVA. The number of human specific copies for HERV-K(HML-2), L1, Alu and SVA families is approx. 150, 1,200, 5,500 and 860 copies per genome, respectively. Taken together, hsTEs shape ∼6.4 megabases of human DNA, which is about 6-times lower than what is occupied by the human specific simple nucleotide polymorphisms, and 23-times smaller than the overall length of human specific deletions and duplications. However, although modest in terms of genomic proportion, hsTEs should be regarded as the perspective candidates for being molecular genetic agents of human speciation. Unlike most of random mutations and duplications, each novel insert of hsTE has provided to the recipient genomic locus a set of functional transcriptional factor binding sites positively selected during the TE evolution. For example, clusters of novel inserts of Alu elements may serve as CpG islets, SVA elements provide functional splice sites and polyadenylation signals, whereas L1 and HERV-K(HML-2) elements donate enhancers, promoters, splice sites and polyadenylation signals. Significant proportion of the human-specific genomic deletions, duplications and translocations has been also generated due to ectopic recombinations between the different individual TE inserts. Among the other, we report for the first time a detailed functional characteristics of the HERV-K(HML-2) hsTEs done at the genome-wide level. We have identified 65 active in vivo human specific promoters contributed by these elements. We also identified three cases of the hsTE-mediated human specific transcriptional regulation of functional protein-coding genes taking part in brain development during embryogenesis. We found ∼180 human specific polyadenylation signals transferred by the SVA elements into the introns of known functional genes. Scaling of these data to the total number of the hsTEs predicts that hundreds of human genes are regulated by these elements. Finally, we discovered the first exclusively human specific TE family, represented by ∼80 members formed by a combination of a part of a CpG islet of human gene MAST2 ansd of the 3′-terminal part of an SVA retrotransposon. According to our estimates, this family, termed CpG-SVA, was far more active than the ancestral SVA family. Our data indicate that MAST2 regulatory sequence was recruited during the evolution to provide effective CpG-SVA transcription in human testicular germ-line cells.