Processes of copy-number change in human DNA: the dynamics of alpha-globin gene deletion. Export

@article{citeulike:695191, abstract = {Ectopic recombination between locally repeated DNA sequences is of fundamental importance in the evolution of gene families, generating copy-number variation in human DNA and often leading to pathological rearrangements. Despite its importance, little is known about the dynamics and processes of these unequal crossovers and the degree to which meiotic recombination plays a role in instability. We address this issue by using as a highly informative system the duplicated alpha-globin genes in which ectopic recombination can lead to gene deletions, often very prevalent in populations affected by malaria, as well as reduplications. Here we show that spontaneous deletions can be accessed directly in genomic DNA by using single-DNA-molecule methods. These deletions proved to be remarkably common in both blood and sperm. Somatic deletions arise by a strictly intrachromosomal pathway of homologous exchange that also operates in the germ line and can generate mutational mosaicism, whereas sperm deletions frequently involve recombinational interactions between homologous chromosomes that most likely occur at meiosis. Ectopic recombination frequencies show surprisingly little requirement for long, identical homology blocks shared by paralogous sequences, and exchanges can occur even between short regions of sequence identity. Finally, direct knowledge of germ-line deletion rates can give insights into the fitness of individuals with these alpha-globin gene deletions, providing a new approach to investigating historical levels of selection operating in human populations.}, author = {Lam, Kwan-Wood W. and Jeffreys, Alec J.}, citeulike-article-id = {695191}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0602690103}, citeulike-linkout-1 = {http://www.pnas.org/cgi/content/abstract/103/24/8921}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/16709669}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=16709669}, day = {13}, doi = {10.1073/pnas.0602690103}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, keywords = {evolution-human, gene\_copy\_number}, month = {June}, number = {24}, pages = {8921--8927}, posted-at = {2006-06-13 20:16:07}, priority = {2}, title = {Processes of copy-number change in human DNA: the dynamics of {alpha}-globin gene deletion.}, url = {http://dx.doi.org/10.1073/pnas.0602690103}, volume = {103}, year = {2006} }

TY - JOUR ID - citeulike:695191 L3 - citeulike-article-id:695191 N2 - Ectopic recombination between locally repeated DNA sequences is of fundamental importance in the evolution of gene families, generating copy-number variation in human DNA and often leading to pathological rearrangements. Despite its importance, little is known about the dynamics and processes of these unequal crossovers and the degree to which meiotic recombination plays a role in instability. We address this issue by using as a highly informative system the duplicated alpha-globin genes in which ectopic recombination can lead to gene deletions, often very prevalent in populations affected by malaria, as well as reduplications. Here we show that spontaneous deletions can be accessed directly in genomic DNA by using single-DNA-molecule methods. These deletions proved to be remarkably common in both blood and sperm. Somatic deletions arise by a strictly intrachromosomal pathway of homologous exchange that also operates in the germ line and can generate mutational mosaicism, whereas sperm deletions frequently involve recombinational interactions between homologous chromosomes that most likely occur at meiosis. Ectopic recombination frequencies show surprisingly little requirement for long, identical homology blocks shared by paralogous sequences, and exchanges can occur even between short regions of sequence identity. Finally, direct knowledge of germ-line deletion rates can give insights into the fitness of individuals with these alpha-globin gene deletions, providing a new approach to investigating historical levels of selection operating in human populations. IS - 24 JF - Proceedings of the National Academy of Sciences of the United States of America SN - 0027-8424 EP - 8927 TI - Processes of copy-number change in human DNA: the dynamics of {alpha}-globin gene deletion. VL - 103 SP - 8921 KW - evolution-human KW - gene_copy_number AU - Lam, Kwan-Wood AU - Jeffreys, Alec PY - 2006/06/13/ UR - http://dx.doi.org/10.1073/pnas.0602690103 ER -