Globin Gene Clusters

Hardison, R

doi:10.1002/0471203076.emm0633

Cited by 2 publications

(5 citation statements)

References 18 publications

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“…Thus, it is of interest that the overall point mutation rate in this region is significantly higher than expected, and that it is significantly higher in the African than in the European population. These facts stand to add to previous, pioneering experimental work on the relevance of locus-specific mutation rates to adaptive evolution and its repeatability (23,24,(26)(27)(28)(29). It has been shown, for example, that high rates of deletion of a pelvic enhancer of the Pitx1 gene are responsible for parallel and likely adaptive loss of the pelvic hindfin in freshwater sticklebacks (26), that mutationally frequent losses or gains of tandem duplicates of agrp2 exon 3 may have been repeatedly involved in color pattern diversification of cichlids (27), and that hypermutability of a HoxA13 duplicate was associated with its neofunctionalization in zebrafish and related taxa (23).…”

Section: Discussionmentioning

confidence: 70%

“…HbS, the most notable mutation variant associated with malarial resistance, is a single base substitution (20A→T) in codon 6 of the HBB coding sequence that causes a Glutamate to Valine change (22)(23)(24). Some other point mutations and short deletions near the HbS site are also known to confer malarial resistance (25,26). δglobin, encoded by the HBD gene, is expressed in adulthood together with HBB (27).…”

Section: Hbb and Hbd Sequence Features Utilized By The Memds Methodsmentioning

confidence: 99%

“…have been reported on HbVar: 16delC, 17 18delCT, 18 19delTG, 19 21delGAG or the equivalent 22 24delGAG (the Hb-Leiden mutation), and 20delA, all in HBB (Table S4). HbVar is an online database that gathers reports of all human hemoglobin variants from the literature and is arguably the largest source of information on this topic (25,26).…”

Section: The Correspondence Between De Novo Rates and Observations Of Alleles In Populationsmentioning

confidence: 99%

“…Table S4: Fold change of observed de novo rates from the genome-wide average (GWA) rates for point mutations in the African HBB ROI. Names of clinically known variants were taken from the Globin Gene Server database (25,26). GWA rates were calculated as described in section 10 based on a subset of de novo mutations with phasing information taken from genomewide family sequencing studies (55) as well as based on relative frequencies of Extremely Rare Variants (ERVs) for the 3-mer, 5-mer and 7-mer genetic contexts (61).…”

Section: T G a C T C C T G A G G A G A A G T T C A Gmentioning

confidence: 99%

“…In particular, rate measurements to date have all been based on averages of various kinds, such as an average across the genome (2,15), across the instances of any particular motif (3,7), or across the entire stretch of a gene in certain cases (16)(17)(18), whereas technological limitations have precluded measuring the mutation rates at particular base positions and of particular mutations at such positions. Such high-resolution knowledge of the mutation-rate variation would bear on multiple open questions in genetics and evolution-from the relative importance of mutation-rate variation to the site frequency spectrum (SFS) (19)(20)(21), to its importance to adaptive evolution and parallelism (22)(23)(24)(25)(26)(27)(28)(29), to its contribution to recurrent genetic disease (30)(31)(32)(33).…”

mentioning

confidence: 99%

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De novomutation rates at the single-mutation resolution in a humanHBBgene-region associated with adaptation and genetic disease

Melamed

Nov

Malik

et al. 2021

Preprint

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While it is known that the mutation rate varies across the genome, previous estimates of it were based on averaging across various numbers of positions. Here we describe a method to measure the origination rates of target mutations at target base positions and apply it to a 6-bp region in the human β–globin (HBB) gene and to the identical, homologous δ–globin (HBD) region in sperm cells from both African and European donors. The HBB region of interest (ROI) includes the site of the hemoglobin S (HbS) mutation, which protects against malaria, is common in Africa and has served as a classic example of adaptation by random mutation and natural selection. We found a significant correspondence between de novo mutation rates and past observations of alleles in carriers, showing that mutation rates vary substantially in a mutation-specific manner that contributes to the site frequency spectrum. We also found that the overall point mutation rate is significantly higher in Africans than Europeans in the HBB region studied. Finally, the rate of the 20A→T mutation, called the ″HbS mutation″ when it appears in HBB, is significantly higher than expected from the genome-wide average for this mutation type. Nine instances of it were observed in the African HBB ROI, where it is of adaptive significance, representing at least three independent originations, and no instances of it were observed in the European HBB ROI or in the European or African HBD ROI. Further studies will be needed to examine mutation rates at the single-mutation resolution across these and other loci and organisms and to uncover the molecular mechanisms responsible.

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Section: Discussionmentioning

confidence: 70%

Section: Hbb and Hbd Sequence Features Utilized By The Memds Methodsmentioning

confidence: 99%

Section: The Correspondence Between De Novo Rates and Observations Of Alleles In Populationsmentioning

confidence: 99%

Section: T G a C T C C T G A G G A G A A G T T C A Gmentioning

confidence: 99%

mentioning

confidence: 99%

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De novomutation rates at the single-mutation resolution in a humanHBBgene-region associated with adaptation and genetic disease

Melamed

Nov

Malik

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

De novo mutation rates at the single-mutation resolution in a human HBB gene region associated with adaptation and genetic disease

et al. 2022

View full text Add to dashboard Cite

While it is known that the mutation rate varies across the genome, previous estimates were based on averaging across various numbers of positions. Here we describe a method to measure the origination rates of target mutations at target base positions and apply it to a 6-bp region in the human hemoglobin subunit beta (HBB) gene and to the identical, paralogous hemoglobin subunit delta (HBD) region in sperm cells from both African and European donors. The HBB region of interest (ROI) includes the site of the hemoglobin S (HbS) mutation, which protects against malaria, is common in Africa and has served as a classic example of adaptation by random mutation and natural selection. We found a significant correspondence between de novo mutation rates and past observations of alleles in carriers, showing that mutation rates vary substantially in a mutation-specific manner that contributes to the site frequency spectrum. We also found that the overall point mutation rate is significantly higher in Africans than in Europeans in the HBB region studied. Finally, the rate of the 20A→T mutation, called the 'HbS mutation' when it appears in HBB, is significantly higher than expected from the genome-wide average for this mutation type. Nine instances were observed in the African HBB ROI, where it is of adaptive significance, representing at least three independent originations; no instances were observed elsewhere. Further studies will be needed to examine mutation rates at the single-mutation resolution across these and other loci and organisms and to uncover the molecular mechanisms responsible.

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Globin Gene Clusters

Cited by 2 publications

References 18 publications

De novomutation rates at the single-mutation resolution in a humanHBBgene-region associated with adaptation and genetic disease

De novomutation rates at the single-mutation resolution in a humanHBBgene-region associated with adaptation and genetic disease

De novo mutation rates at the single-mutation resolution in a human HBB gene region associated with adaptation and genetic disease

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