Signatures of rapid change in PRDM9 binding targets are evident in archaic humans

Objectives: Multiple lines of evidence suggest that the rapidly evolving zinc-finger (ZF) protein, PRDM9, is responsible for initiating much or all of recombination in human. PRDM9 shows extreme variation in both the number and sequence of its ZFs, between species and amongst individuals, across mam...

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Main Authors:	Tumian, Afidalina, Davies, Robert W., Myers, Simon
Format:	Conference or Workshop Item
Language:	English
Published:	2015
Subjects:	Q Science (General)
Online Access:	http://irep.iium.edu.my/47189/ http://irep.iium.edu.my/47189/ http://irep.iium.edu.my/47189/1/47189.pdf

id	iium-47189
recordtype	eprints
spelling	iium-471892017-12-29T02:16:40Z http://irep.iium.edu.my/47189/ Signatures of rapid change in PRDM9 binding targets are evident in archaic humans Tumian, Afidalina Davies, Robert W. Myers, Simon Q Science (General) Objectives: Multiple lines of evidence suggest that the rapidly evolving zinc-finger (ZF) protein, PRDM9, is responsible for initiating much or all of recombination in human. PRDM9 shows extreme variation in both the number and sequence of its ZFs, between species and amongst individuals, across mammals. The rapid evolution of the PRDM9 ZF array may be a response to escape a self-destructive drive called biased gene conversion (BGC), which can cause preferential transmission of hotspot disrupting alleles, and leading to erosion of vital recombination sites in the genome through time. Using the recent available Neanderthal and Denisovan high quality genomes, we developed statistical methods that identify the locations where meiotic recombination could have occurred in the past. This is achieved by looking for short words that have undergone rapid losses or gains in each lineage. Methods: In particular, the statistical framework involves an enumerative approach that scans genomewide archaic human genomes which have been mapped to a 6-way primate alignment, exhaustively catalogues all short exact motifs, and identifies statistically highly evolved words. Results: Across all species, remarkably, we observed definitive evidence that on each lineage, specific genomic "words" have been rapidly removed from the genome, at rates highly inconsistent with neutral mutation changes. It seemed possible that they might have been past binding targets of PRDM9, with rapid evolution of the PRDM9 zinc finger array explaining their lineage-specificity, and differences in PRDM9 binding explaining the stronger signals in specific genomic regions. As predicted by BGC, we saw an overwhelming support for bias towards acceleration of motif loss rather than motif gain. In human lineage, it is shown that the method almost successfully identifies the current human hotspot motif, CCNCCNTNNCCNC. Conclusion: It is suggestive that we are able to see positions of ancient hotspots, and could even make maps of ancient hotspot positions, by looking at the distribution of motif losses along the genomes. The findings could further shed light on the dynamic turnover of PRDM9 binding sites, and help understand the details of how recombination has shaped over genomes. 2015-03-14 Conference or Workshop Item NonPeerReviewed application/pdf en http://irep.iium.edu.my/47189/1/47189.pdf Tumian, Afidalina and Davies, Robert W. and Myers, Simon (2015) Signatures of rapid change in PRDM9 binding targets are evident in archaic humans. In: Human Genome Meeting 2015 (HGM 2015), 14th-17th March 2015, Kuala Lumpur Convention Centre, Kuala Lumpur. (Unpublished) http://www.hugo-international.org/Resources/Documents/HGM2015_Final%20Programme%20and%20Abstract%20Book.pdf
repository_type	Digital Repository
institution_category	Local University
institution	International Islamic University Malaysia
building	IIUM Repository
collection	Online Access
language	English
topic	Q Science (General)
spellingShingle	Q Science (General) Tumian, Afidalina Davies, Robert W. Myers, Simon Signatures of rapid change in PRDM9 binding targets are evident in archaic humans
description	Objectives: Multiple lines of evidence suggest that the rapidly evolving zinc-finger (ZF) protein, PRDM9, is responsible for initiating much or all of recombination in human. PRDM9 shows extreme variation in both the number and sequence of its ZFs, between species and amongst individuals, across mammals. The rapid evolution of the PRDM9 ZF array may be a response to escape a self-destructive drive called biased gene conversion (BGC), which can cause preferential transmission of hotspot disrupting alleles, and leading to erosion of vital recombination sites in the genome through time. Using the recent available Neanderthal and Denisovan high quality genomes, we developed statistical methods that identify the locations where meiotic recombination could have occurred in the past. This is achieved by looking for short words that have undergone rapid losses or gains in each lineage. Methods: In particular, the statistical framework involves an enumerative approach that scans genomewide archaic human genomes which have been mapped to a 6-way primate alignment, exhaustively catalogues all short exact motifs, and identifies statistically highly evolved words. Results: Across all species, remarkably, we observed definitive evidence that on each lineage, specific genomic "words" have been rapidly removed from the genome, at rates highly inconsistent with neutral mutation changes. It seemed possible that they might have been past binding targets of PRDM9, with rapid evolution of the PRDM9 zinc finger array explaining their lineage-specificity, and differences in PRDM9 binding explaining the stronger signals in specific genomic regions. As predicted by BGC, we saw an overwhelming support for bias towards acceleration of motif loss rather than motif gain. In human lineage, it is shown that the method almost successfully identifies the current human hotspot motif, CCNCCNTNNCCNC. Conclusion: It is suggestive that we are able to see positions of ancient hotspots, and could even make maps of ancient hotspot positions, by looking at the distribution of motif losses along the genomes. The findings could further shed light on the dynamic turnover of PRDM9 binding sites, and help understand the details of how recombination has shaped over genomes.
format	Conference or Workshop Item
author	Tumian, Afidalina Davies, Robert W. Myers, Simon
author_facet	Tumian, Afidalina Davies, Robert W. Myers, Simon
author_sort	Tumian, Afidalina
title	Signatures of rapid change in PRDM9 binding targets are evident in archaic humans
title_short	Signatures of rapid change in PRDM9 binding targets are evident in archaic humans
title_full	Signatures of rapid change in PRDM9 binding targets are evident in archaic humans
title_fullStr	Signatures of rapid change in PRDM9 binding targets are evident in archaic humans
title_full_unstemmed	Signatures of rapid change in PRDM9 binding targets are evident in archaic humans
title_sort	signatures of rapid change in prdm9 binding targets are evident in archaic humans
publishDate	2015
url	http://irep.iium.edu.my/47189/ http://irep.iium.edu.my/47189/ http://irep.iium.edu.my/47189/1/47189.pdf
first_indexed	2023-09-18T21:07:10Z
last_indexed	2023-09-18T21:07:10Z
_version_	1777411010958721024

Signatures of rapid change in PRDM9 binding targets are evident in archaic humans

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