Abstract:
:We studied mutations in the mtDNA control region (CR) using deep-rooting French-Canadian pedigrees. In 508 maternal transmissions, we observed four substitutions (0.0079 per generation per 673 bp, 95% CI 0.0023-0.186). Combined with other familial studies, our results add up to 18 substitutions in 1,729 transmissions (0.0104), confirming earlier findings of much greater mutation rates in families than those based on phylogenetic comparisons. Only 12 of these mutations occurred at independent sites, whereas three positions mutated twice each, suggesting that pedigree studies preferentially reveal a fraction of highly mutable sites. Fitting the data through use of a nonuniform rate model predicts the presence of 40 (95% CI 27-54) such fast sites in the whole CR, characterized by the mutation rate of 274 per site per million generations (95% CI 138-410). The corresponding values for hypervariable regions I (HVI; 1,729 transmissions) and II (HVII; 1,956 transmissions), are 19 and 22 fast sites, with rates of 224 and 274, respectively. Because of the high probability of recurrent mutations, such sites are expected to be of no or little informativity for the evaluation of mutational distances at the phylogenetic time scale. The analysis of substitution density in the alignment of 973 HVI and 650 HVII unrelated European sequences reveals that the bulk of the sites mutate at relatively moderate and slow rates. Assuming a star-like phylogeny and an average time depth of 250 generations, we estimate the rates for HVI and HVII at 23 and 24 for the moderate sites and 1.3 and 1.0 for the slow sites. The fast, moderate, and slow sites, at the ratio of 1:2:13, respectively, describe the mutation-rate heterogeneity in the CR. Our results reconcile the controversial rate estimates in the phylogenetic and familial studies; the fast sites prevail in the latter, whereas the slow and moderate sites dominate the phylogenetic-rate estimations.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Heyer E,Zietkiewicz E,Rochowski A,Yotova V,Puymirat J,Labuda Ddoi
10.1086/324024subject
Has Abstractpub_date
2001-11-01 00:00:00pages
1113-26issue
5eissn
0002-9297issn
1537-6605pii
S0002-9297(07)61326-3journal_volume
69pub_type
杂志文章abstract::Diabetes mellitus and neurodegeneration are common diseases for which shared genetic factors are still only partly known. Here, we show that loss of the BiP (immunoglobulin heavy-chain binding protein) co-chaperone DNAJC3 leads to diabetes mellitus and widespread neurodegeneration. We investigated three siblings with ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2014.10.013
更新日期:2014-12-04 00:00:00
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pub_type: 评论,杂志文章
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abstract::Transthyretin (TTR) (122 Val----Ile), caused by a point mutation which destroys a MaeIII restriction site, is associated with cardiac amyloidosis in black individuals. To estimate the frequency of the MaeIII(-) gene in the black population without overt cardiac disease, DNA from 177 black individuals without amyloidos...
journal_title:American journal of human genetics
pub_type: 杂志文章,评审
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/382285
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1991-04-01 00:00:00
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1996-04-01 00:00:00
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/302888
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pub_type: 杂志文章
doi:10.1016/j.ajhg.2019.09.017
更新日期:2019-11-07 00:00:00
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2008.02.016
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journal_title:American journal of human genetics
pub_type: 杂志文章
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/498853
更新日期:2006-01-01 00:00:00
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1986-07-01 00:00:00
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journal_title:American journal of human genetics
pub_type: 杂志文章,评审
doi:10.1086/432962
更新日期:2005-09-01 00:00:00
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1994-03-01 00:00:00
abstract::Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzi...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2020.12.007
更新日期:2021-01-04 00:00:00
abstract::An expansion of an unstable (CTG)n trinucleotide repeat in the 3' UTR of a gene encoding a putative serine/threonine protein kinase (DMPK) on human chromosome 19q13.3 has been shown to be specific for the myotonic dystrophy (DM) disease phenotype. In addition, a single haplotype composed of nine alleles within and fla...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1995-05-01 00:00:00
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/426953
更新日期:2005-01-01 00:00:00
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2019.07.020
更新日期:2019-09-05 00:00:00
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1986-09-01 00:00:00
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journal_title:American journal of human genetics
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journal_title:American journal of human genetics
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doi:
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1990-06-01 00:00:00
abstract::Chiasma frequency data on 183 males were subjected to an analysis of covariance. There appeared to be little or no linear trend in chiasma frequency with age. This conclusion was supported by a detailed analysis of chiasma frequencies for each autosome from 21 males. There were, however, significant differences among ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1975-05-01 00:00:00
abstract::The decreasing cost of whole-genome and whole-exome sequencing has resulted in a renaissance for identifying Mendelian disease mutations, and for the first time it is possible to survey the distribution and characteristics of these mutations in large population samples. We conducted carrier screening for all autosomal...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2012.08.007
更新日期:2012-10-05 00:00:00
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1977-03-01 00:00:00
abstract::A stepwise logistic-regression procedure is proposed for evaluation of the relative importance of variants at different sites within a small genetic region. By fitting statistical models with main effects, rather than modeling the full haplotype effects, we generate tests, with few degrees of freedom, that are likely ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/338007
更新日期:2002-01-01 00:00:00
abstract::The gene(s) whose expression is regulated by allergy risk variants is unknown for many loci identified through genome-wide association studies. Addressing this knowledge gap might point to new therapeutic targets for allergic disease. The aim of this study was to identify the target gene(s) and the functional variant(...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2015.06.010
更新日期:2015-08-06 00:00:00
abstract::The introduction of stochastic methods in pedigree analysis has enabled geneticists to tackle computations intractable by standard deterministic methods. Until now these stochastic techniques have worked by running a Markov chain on the set of genetic descent states of a pedigree. Each descent state specifies the path...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1996-06-01 00:00:00
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/302957
更新日期:2000-07-01 00:00:00