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The fragility of a structurally diverse duplication block triggers recurrent genomic amplification.

ABSTRACT: The human genome contains hundreds of large, structurally diverse blocks that are insufficiently represented in the reference genome and are thus not amenable to genomic analyses. Structural diversity in the human population suggests that these blocks are unstable in the germline; however, whether or not these blocks are also unstable in the cancer genome remains elusive. Here we report that the 500 kb block called KRTAP_region_1 (KRTAP-1) on 17q12-21 recurrently demarcates the amplicon of the ERBB2 (HER2) oncogene in breast tumors. KRTAP-1 carries numerous tandemly-duplicated segments that exhibit diversity within the human population. We evaluated the fragility of the block by cytogenetically measuring the distances between the flanking regions and found that spontaneous distance outliers (i.e DNA breaks) appear more frequently at KRTAP-1 than at the representative common fragile site (CFS) FRA16D. Unlike CFSs, KRTAP-1 is not sensitive to aphidicolin. The exonuclease activity of DNA repair protein Mre11 protects KRTAP-1 from breaks, whereas CtIP does not. Breaks at KRTAP-1 lead to the palindromic duplication of the ERBB2 locus and trigger Breakage-Fusion-Bridge cycles. Our results indicate that an insufficiently investigated area of the human genome is fragile and could play a crucial role in cancer genome evolution.

SUBMITTER: Suzuki R

PROVIDER: S-EPMC7797068 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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The fragility of a structurally diverse duplication block triggers recurrent genomic amplification.

Suzuki Ryusuke R Murata Michael M MM Manguso Nicholas N Watanabe Takaaki T Mouakkad-Montoya Lila L Igari Fumie F Rahman Md Maminur MM Qu Ying Y Cui Xiaojiang X Giuliano Armando E AE Takeda Shunichi S Tanaka Hisashi H

Nucleic acids research 20210101 1

The human genome contains hundreds of large, structurally diverse blocks that are insufficiently represented in the reference genome and are thus not amenable to genomic analyses. Structural diversity in the human population suggests that these blocks are unstable in the germline; however, whether or not these blocks are also unstable in the cancer genome remains elusive. Here we report that the 500 kb block called KRTAP_region_1 (KRTAP-1) on 17q12-21 recurrently demarcates the amplicon of the E ...[more]

PMID: 33290559

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Project description:BackgroundConvergent and parallel evolution provide unique insights into the mechanisms of natural selection. Some of the most striking convergent and parallel (collectively recurrent) amino acid substitutions in proteins are adaptive, but there are also many that are selectively neutral. Accordingly, genome-wide assessment has shown that recurrent sequence evolution in orthologs is chiefly explained by nearly neutral evolution. For paralogs, more frequent functional change is expected because additional copies are generally not retained if they do not acquire their own niche. Yet, it is unknown to what extent recurrent sequence differentiation is discernible after independent gene duplications in different eukaryotic taxa.ResultsWe develop a framework that detects patterns of recurrent sequence evolution in duplicated genes. This is used to analyze the genomes of 90 diverse eukaryotes. We find a remarkable number of families with a potentially predictable functional differentiation following gene duplication. In some protein families, more than ten independent duplications show a similar sequence-level differentiation between paralogs. Based on further analysis, the sequence divergence is found to be generally asymmetric. Moreover, about 6% of the recurrent sequence evolution between paralog pairs can be attributed to recurrent differentiation of subcellular localization. Finally, we reveal the specific recurrent patterns for the gene families Hint1/Hint2, Sco1/Sco2 and vma11/vma3.ConclusionsThe presented methodology provides a means to study the biochemical underpinning of functional differentiation between paralogs. For instance, two abundantly repeated substitutions are identified between independently derived Sco1 and Sco2 paralogs. Such identified substitutions allow direct experimental testing of the biological role of these residues for the repeated functional differentiation. We also uncover a diverse set of families with recurrent sequence evolution and reveal trends in the functional and evolutionary trajectories of this hitherto understudied phenomenon.

Dataset Information

The fragility of a structurally diverse duplication block triggers recurrent genomic amplification.

Publications

The fragility of a structurally diverse duplication block triggers recurrent genomic amplification.

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