The functional and evolutionary impacts of human-specific deletions in conserved elements
[INTRODUCTION] Deciphering the molecular and genetic changes that differentiate humans from our closest primate relatives is critical for understanding our origins. Although earlier studies have prioritized how newly gained genetic sequences or variations have contributed to evolutionary innovation, the role of sequence loss has been less appreciated. Alterations in evolutionary conserved regions that are enriched for biological function could be particularly more likely to have phenotypic effects. We thus sought to identify and characterize sequences that have been conserved across evolution, but are then surprisingly lost in all humans. These human-specific deletions in conserved regions (hCONDELs) may play an important role in uniquely human traits.
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American Association for the Advancement of Science
2023-04-28
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[INTRODUCTION] Deciphering the molecular and genetic changes that differentiate humans from our closest primate relatives is critical for understanding our origins. Although earlier studies have prioritized how newly gained genetic sequences or variations have contributed to evolutionary innovation, the role of sequence loss has been less appreciated. Alterations in evolutionary conserved regions that are enriched for biological function could be particularly more likely to have phenotypic effects. We thus sought to identify and characterize sequences that have been conserved across evolution, but are then surprisingly lost in all humans. These human-specific deletions in conserved regions (hCONDELs) may play an important role in uniquely human traits. |
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Howard Hughes Medical Institute |
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Howard Hughes Medical Institute Xue, James R. Mackay-Smith, Ava Mouri, Kousuke Fernandez Garcia, Meilin Dong, Michael X. Akers, Jared F. Noble, Mark Li, Xue Zoonomia Consortium Juan, David Marqués-Bonet, Tomàs Muntané, Gerard Navarro, Arcadi Serres-Armero, Aitor Valenzuela, Alejandro Lindblad-Toh, Kerstin Karlsson, Elinor K. Noonan, James P. Capellini, Terence D. Brennand, Kristen J. Tewhey, Ryan Sabeti, Pardis C. Reilly, Steven K. |
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artículo |
| author |
Xue, James R. Mackay-Smith, Ava Mouri, Kousuke Fernandez Garcia, Meilin Dong, Michael X. Akers, Jared F. Noble, Mark Li, Xue Zoonomia Consortium Juan, David Marqués-Bonet, Tomàs Muntané, Gerard Navarro, Arcadi Serres-Armero, Aitor Valenzuela, Alejandro Lindblad-Toh, Kerstin Karlsson, Elinor K. Noonan, James P. Capellini, Terence D. Brennand, Kristen J. Tewhey, Ryan Sabeti, Pardis C. Reilly, Steven K. |
| spellingShingle |
Xue, James R. Mackay-Smith, Ava Mouri, Kousuke Fernandez Garcia, Meilin Dong, Michael X. Akers, Jared F. Noble, Mark Li, Xue Zoonomia Consortium Juan, David Marqués-Bonet, Tomàs Muntané, Gerard Navarro, Arcadi Serres-Armero, Aitor Valenzuela, Alejandro Lindblad-Toh, Kerstin Karlsson, Elinor K. Noonan, James P. Capellini, Terence D. Brennand, Kristen J. Tewhey, Ryan Sabeti, Pardis C. Reilly, Steven K. The functional and evolutionary impacts of human-specific deletions in conserved elements |
| author_sort |
Xue, James R. |
| title |
The functional and evolutionary impacts of human-specific deletions in conserved elements |
| title_short |
The functional and evolutionary impacts of human-specific deletions in conserved elements |
| title_full |
The functional and evolutionary impacts of human-specific deletions in conserved elements |
| title_fullStr |
The functional and evolutionary impacts of human-specific deletions in conserved elements |
| title_full_unstemmed |
The functional and evolutionary impacts of human-specific deletions in conserved elements |
| title_sort |
functional and evolutionary impacts of human-specific deletions in conserved elements |
| publisher |
American Association for the Advancement of Science |
| publishDate |
2023-04-28 |
| url |
http://hdl.handle.net/10261/348713 |
| work_keys_str_mv |
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1792484742919094272 |
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dig-ibe-es-10261-3487132024-02-29T07:26:30Z The functional and evolutionary impacts of human-specific deletions in conserved elements Xue, James R. Mackay-Smith, Ava Mouri, Kousuke Fernandez Garcia, Meilin Dong, Michael X. Akers, Jared F. Noble, Mark Li, Xue Zoonomia Consortium Juan, David Marqués-Bonet, Tomàs Muntané, Gerard Navarro, Arcadi Serres-Armero, Aitor Valenzuela, Alejandro Lindblad-Toh, Kerstin Karlsson, Elinor K. Noonan, James P. Capellini, Terence D. Brennand, Kristen J. Tewhey, Ryan Sabeti, Pardis C. Reilly, Steven K. Howard Hughes Medical Institute Stanford University Broad Institute National Institutes of Health (US) University of Massachusetts Swedish Medical Research Council [INTRODUCTION] Deciphering the molecular and genetic changes that differentiate humans from our closest primate relatives is critical for understanding our origins. Although earlier studies have prioritized how newly gained genetic sequences or variations have contributed to evolutionary innovation, the role of sequence loss has been less appreciated. Alterations in evolutionary conserved regions that are enriched for biological function could be particularly more likely to have phenotypic effects. We thus sought to identify and characterize sequences that have been conserved across evolution, but are then surprisingly lost in all humans. These human-specific deletions in conserved regions (hCONDELs) may play an important role in uniquely human traits. [RATIONALE] Sequencing advancements have identified millions of genetic changes between chimpanzee and human genomes; however, the functional impacts of the ~1 to 5% difference between our species is largely unknown. hCONDELs are one class of these predominantly noncoding sequence changes. Although large hCONDELs (>1 kb) have been previously identified, the vast majority of all hCONDELs (95.7%) are small (<20 base pairs) and have not yet been functionally assessed. We adapted massively parallel reporter assays (MPRAs) to characterize the effects of thousands of these small hCONDELs and uncovered hundreds with functional effects. By understanding the effects of these hCONDELs, we can gain insight into the mechanistic patterns driving evolution in the human genome. [RESULTS] We identified 10,032 hCONDELs by examining conserved regions across diverse vertebrate genomes and overlapping with confidently annotated, human-specific fixed deletions. We found that these hCONDELs are enriched to delete conserved sequences originating from stem amniotes. Overlap with transcriptional, epigenomic, and phenotypic datasets all implicate neuronal and cognitive functional impacts. We characterized these hCONDELs using MPRA in six different human cell types, including induced pluripotent stem cell–derived neural progenitor cells. We found that 800 hCONDELs displayed species-specific regulatory effect effects. Although many hCONDELs perturb transcription factor–binding sites in active enhancers, we estimate that 30% create or improve binding sites, including activators and repressors. Some hCONDELs exhibit molecular functions that affect core neurodevelopmental genes. One hCONDEL removes a single base in an active enhancer in the neurogenesis gene HDAC5, and another deletes six bases in an alternative promoter of PPP2CA, a gene that regulates neuronal signaling. We deeply characterized an hCONDEL in a putative regulatory element of LOXL2, a gene that controls neuronal differentiation. Using genome engineering to reintroduce the conserved chimpanzee sequence into human cells, we confirmed that the human deletion alters transcriptional output of LOXL2. Single-cell RNA sequencing of these cells uncovered a cascade of myelination and synaptic function–related transcriptional changes induced by the hCONDEL. [CONCLUSION] Our identification of hundreds of hCONDELs with functional impacts reveals new molecular changes that may have shaped our unique biological lineage. These hCONDELs display predicted functions in a variety of biological systems but are especially enriched for function in neuronal tissue. Many hCONDELs induced gains of regulatory activity, a surprising discovery given that deletions of conserved bases are commonly thought to abrogate function. Our work provides a paradigm for the characterization of nucleotide changes shaping species-specific biology across humans or other animals. This work was supported by the ENCODE Functional Characterization Center (grant UM1 HG009435 to P.C.S., R.T., and S.K.R.); Broad SPARC (P.C.S.); Howard Hughes Medical Institute (P.C.S.); and the National Institutes of Health (grant R00HG010669 to S.K.R., grants R00HG008179 and R35HG011329 to R.T., grant RF1AG065926 to M.F.G. and K.J.B., grant R01MH125246 to M.F.G. and K.J.B., grant R56MH125237 to M.F.G. and K.J.B., grant 5T32MH014276-45 to M.F.G., and grant R01HG008742 to E.K.); the Liweibo PhD scholarship from the University of Massachusetts Chan Medical School (X.L.); and the Distinguished professor award from the Swedish Medical Research Council (K.L.T.). Peer reviewed 2024-02-29T07:26:30Z 2024-02-29T07:26:30Z 2023-04-28 artículo Science 380: eabn2253 (2023) 0036-8075 http://hdl.handle.net/10261/348713 10.1126/science.abn2253 1095-9203 en https://doi.org/10.1126/science.abn2253 Sí none American Association for the Advancement of Science |