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PubMed2006

Genomic and evolutionary insights into genes encoding proteins with single amino acid repeats.

Mutations causing expansion of amino acid repeats are responsible for 19 hereditary disorders. Repeats in several other proteins also show length variations. These observations prompted us to identify single amino acid repeat-containing proteins (SARPs) in humans and to understand their functional and evolutionary significance. We identified 8812 SARPs containing 17 146 repeat domains, each harboring 4 or more residues. In all, 5% of SARPs (471) showed repeat length variations, and nearly 84% of them (394) have repeats of 10 residues or less. We find that SARPs are involved in functions that require formation of multiprotein complexes. Nearly 78% (6859) of the SARPs did not find a paralogue in the human proteome, and such proteins are considered as orphan SARPs. Orphan SARPs show longer repeat stretches, longer peptide length, and lower expression levels as compared with SARPs belonging to protein family. Because the intensity of gene expression is known to relate inversely with the rate of protein sequence evolution, our results suggest that the orphan SARPs evolve faster than the familial forms and therefore are under a weaker selection pressure. We also find that while GC-rich codons are favored for coding the repeat tracts of SARPs, specific codons and not nucleotide motifs per se are selected, suggesting functional constraints placed on the usage of codons. One of the constraints could be the mRNA stability as clustering of rare codons is known to destabilize the transcripts and rare codons are not favored for coding repeat tracts. Genes encoding polymorphic SARPs show preferential localization toward the telomeric segments. Further, the sex-specific recombination rates of the chromosomal locus strongly correlate with the parental gender that influence the repeat instability in disorder caused by dynamic mutation. Therefore, instability associated with repeats might be driven by processes that are specific to sperm or oocyte development, and the recombination frequency might play a positive role in this process.

Base Sequence↗
PubMedDate not supplied

[Importance of the number of trinucleotide repeat expansions in the clinical manifestations of Huntington's chorea].

INTRODUCTION: In 1993 the gene responsible for Huntington's disease (IT15) was isolated [5]. It was mapped to the tip of the short arm of chromosome 4 and within its coding sequence, near the 5' end, it contained a certain number of trinicleotide (CAG)n (cytosine-adenine-guanine) repeats (Figure 1). This gene codes for a protein (348 kd) called "huntington" that is widely expressed, and its sequence is not related to any protein [6]. The normal range of (CAG)n repeat numbers within IT15 was reported to be between 6 and 37 [6]. Mutation responsible for Huntington's disease implied expansion of (CAG)n repeats: in patients with Huntington's disease the pathologic range was determined to be between 35 and 121 repeats [7-10]. PATIENTS AND METHODS: In this study we correlated the age at onset, rate of progression and initial symptoms of Huntington's disease with the number of trinucleotide (CAG)n repeats in IT15. DNA was isolated from peripheral blood leukocytes of patients fulfilling clinical criteria for definite and probable Huntington's disease [2]. Genetic verification of Huntington's disease was made by the previously described and modified PRC (polymerase chain reaction) technique [17, 18]. In our laboratory a gene with 40 or more repeats was considered as a marker of Huntington's disease. RESULTS: The study comprised 26 patients (11 women and 15 men). At the onset of Huntington's disease they were between 19 and 66 years old (36.6 12.8 years), with the duration of the disease between 1 and 15 years (5.8 4.3 years). The number of (CAG)n, repeats in IT15 ranged between 40 and 95 (49.9 14.1). The negative correlation between the (CAG)n, count in the expanded allele and the age at onset of the disease has been confirmed. Regression analysis showed the correlation coefficient of -0.54 (p = 0.012). The effect of trinucleotide (CAG)n, repeats on the initial clinical manifestations and rate of progression of Huntington's disease is only one of the growing group of "CAG-repeat" disorders that also include entities such as spinocerebellar ataxia-type 1 and 3, spinobulbar muscular atrophy and dentato-rubo-pallidoluysian atrophy [6].

Adult↗
PubMed2026

Are we Prepared? Genetic Counseling for Stillbirth in the Sequencing Era.

Stillbirth affects approximately 1 in 175 pregnancies annually in the United States. Although the American College of Obstetricians and Gynecologists recommends genetic testing as part of the stillbirth evaluation, families often face barriers to obtaining a complete evaluation. Expansion of the diagnostic evaluation of stillbirth is expected to include exome/genome sequencing, with preliminary studies demonstrating its diagnostic utility. Consequently, genetic counselors (GCs) are expected to play an expanding role in post-stillbirth care. This study explored current genetic counseling practices for stillbirth and GCs' preparedness to support patients in this setting. A cross-sectional survey was distributed across four channels. Eligible participants included GCs in the United States and Canada with at least 1 year of prenatal experience. The survey assessed GC frequency and timing in stillbirth counseling, genetic testing practices, comfort addressing psychosocial needs, and perceived barriers to care. Responses were analyzed using descriptive statistics. Group comparisons were performed using Chi-square and Fisher's exact tests. Open-ended responses were coded for themes. Seventy-one responses were analyzed. Approximately half of respondents (49.3%, n = 36) reported "never/very rarely/rarely" counseling patients postpartum, despite this being the optimal time to offer genetic testing. Delivering providers (46.5%, n = 33) were often responsible for informing patients about testing and obtaining consent, compared to GCs (11.3%, n = 8). Although chromosomal microarray (CMA) is recommended as the standard of care (SOC), 12.7% (n = 9) of GCs reported not offering CMA for anomalous and non-anomalous stillbirths. Perceived barriers to SOC testing included reported lack of obstetrician awareness (91.5%, n = 65) and challenges coordinating specimen collection (90.1%, n = 64). These findings highlight barriers to SOC genetic evaluation and underscore the need to strengthen institutional protocols, enhance provider education, and develop stillbirth-specific genetic counseling guidelines. GC involvement in these efforts will be essential to promoting equitable access to comprehensive post-stillbirth care as sequencing becomes integrated into practice.

Humans↗
PubMed1990

Modulation of intercellular communication during radiation and chemical carcinogenesis.

Carcinogenesis is a multistep process, involving the irreversible conversion of a stem cell to a terminal-differentiation-resistant cell ("initiation"), followed by the clonal expansion of this cell ("promotion") and by the acquisition of other genetic alterations leading to malignancy ("progression"). The initiation and progression steps seem to be facilitated by mutagenesis. Promotion has been associated with agents and conditions that cause mitogenesis. Gap junctional intercellular communication, a fundamental biological process regulating cell growth and differentiation, has been postulated to play a major role in carcinogenesis. The hypothesis is supported by the fact that many cancer cells have some dysfunction in gap junctional intercellular communication, many tumor-promoting chemicals and several oncogenes (i.e., ras, src, mos, neu, but not myc) reduce gap junctional intercellular communication, and several growth factors (i.e., EGF, TGF-beta, bovine pituitary extract) inhibit gap junction function. This integrative concept postulates that chemical promoters, oncogenes coding for growth factors, receptors, or transmembrane signaling elements, and growth factors can isolate an initiated cell from the suppressing influence of surrounding normal cells by down-regulating the transfer of ions and small molecules through gap junctions.

Animals↗
PubMed2004

MtDNA profile of West Africa Guineans: towards a better understanding of the Senegambia region.

The matrilineal genetic composition of 372 samples from the Republic of Guiné-Bissau (West African coast) was studied using RFLPs and partial sequencing of the mtDNA control and coding region. The majority of the mtDNA lineages of Guineans (94%) belong to West African specific sub-clusters of L0-L3 haplogroups. A new L3 sub-cluster (L3h) that is found in both eastern and western Africa is present at moderately low frequencies in Guinean populations. A non-random distribution of haplogroups U5 in the Fula group, the U6 among the "Brame" linguistic family and M1 in the Balanta-Djola group, suggests a correlation between the genetic and linguistic affiliation of Guinean populations. The presence of M1 in Balanta populations supports the earlier suggestion of their Sudanese origin. Haplogroups U5 and U6, on the other hand, were found to be restricted to populations that are thought to represent the descendants of a southern expansion of Berbers. Particular haplotypes, found almost exclusively in East-African populations, were found in some ethnic groups with an oral tradition claiming Sudanese origin.

Black People↗
PubMed1999

An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8)

Myotonic dystrophy (DM) is the only disease reported to be caused by a CTG expansion. We now report that a non-coding CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). This expansion, located on chromosome 13q21, was isolated directly from the genomic DNA of an ataxia patient by RAPID cloning. SCA8 patients have expansions similar in size (107-127 CTG repeats) to those found among adult-onset DM patients. SCA8 is the first example of a dominant SCA not caused by a CAG expansion translated as a polyglutamine tract.

Alleles↗
PubMed1997

Polymorphic trinucleotide repeat in the MEF2A gene at 15q26 is not expanded in familial cardiomyopathies.

A trinucleotide repeat polymorphism in the MEF2A gene is described. MEF2A is expressed early in cardiac muscle development; thus the possibility of linkage between this polymorphism and familial cardiomyopathies was investigated in three families not linked to genes coding for known sarcomeric proteins. MEF2A was excluded as a candidate for dilated cardiomyopathy (DCM)(LOD of -9.03) and hypertrophic cardiomyopathy (HCM)(LODs of -5.43 and -2.44) in these families. Because expansion of triplet repeats has been shown to be responsible for several inherited diseases, 121 unrelated HCM probands and 28 unrelated DCM probands were examined for evidence of expansion of this repeat. No expansion of this trinucleotide repeat was seen in any of the 149 cardiomyopathy probands.

Alleles↗
PubMed2006

An unusual phylogeography in the bushcricket Ephippiger ephippiger from Southern France.

Pleistocene glaciations have played a major role in species divergence. The bushcricket Ephippiger ephippiger shows unusual patterns of intraspecific variation in multiple traits across Southern Europe. This is centred in Southern France, and evidence implies that it results from secondary contact after differentiation in Pleistocene refugia. However, the possible time scales involved, locations of the refugia and patterns of expansion remain obscure. This study sequenced the COII (507 BP) and cyt b (428 BP) mitochondrial genes to examine the intraspecific phylogeography of Western European samples of E. ephippiger. A minimum evolution tree revealed little resolution between described subspecies of E. ephippiger. Strikingly, populations from the Pyrenees and Mediterranean coastal region contained a complex genetic structure corresponding to major river valleys, independent of the traditional taxonomy. Samples of the subspecies E. e. vitium formed a distinct clade, perhaps supporting their taxonomic status. However, other forms (cruciger and cunii) were not genetically distinct, which is surprising given differences in their morphology and behaviour. The extent of the genetic divergence between Pyreneen valleys is unexpectedly deep, with average Tamura-Nei distances of around 14% (net distances of 11%) separating the main clades of coding COII sequences. Cyt b showed a similar pattern, but was confounded by some non-coding probable pseudogenes. If a conventional insect molecular clock is applied, these cryptic clades must pre-date the Pleistocene, and hypotheses for their history are discussed. However, mtDNA divergence in Ephippiger is not evolving in a clock-like manner, because a likelihood ratio test rejects clock assumptions for the COII sequences.

Animals↗
PubMed2002

[Proteins and mutations: a new vision (molecular) of neurodegenerative diseases].

Neurodegenerative diseases have long been considered to be poorly defined, misunderstood, and inadequately treated. In recent years, research on Alzheimer's disease has led to numerous advances that have improved our understanding of this form of dementia and also of the entire category of neurodegenerative diseases. It now appears that numerous neurodegenerative diseases of the central nervous system correspond to the aggregation of specific proteins: beta-amyloid in Alzheimer disease, tau protein in Alzheimer disease, fronto-temporal dementia, progressive supranuclear palsy and corticobasal degeneration, alpha-synuclein in Parkinson disease and Lewy body dementia, PrP protein in prion diseases, SOD in amyotrophic lateral sclerosis, polyglutamine expansions in Huntington's disease and other diseases, etc. It is remarkable that in all these cases mutations have been identified for genes coding for these proteins and able to cause the disease and, moreover, that the introduction of the corresponding gene into transgenic mice (or other transgenic animals) has made it possible to create animal models of these conditions. This suggests that the proteins in question play a determinative role in the pathogenesis of these diseases and are not simply consequences of it. Neurodegenerative diseases are proteinopathies. But they are also networkopathies because the neuronal proteins are organized in functional networks. We must also note that all these diseases are associated with the process of aging, for they do not appear in the young. This fact suggests that the anomaly (genetic or otherwise) concerning a given protein does not suffice by itself to induce the disease process. Many observations suggest that the additional event involved, common to all neurodegenerative conditions, may be the intervention of free radicals. We thus propose here the theory that the diversity of neurodegenerative diseases is explained by the combination of two pathogenic events: one specific and associated with the aggregation of a particular protein in the nervous system, the other, non-specific and associated with aging and with the production and harmful actions of free radicals. This unified interpretation leads directly to treatment hypotheses: the development of drugs capable either of inhibiting the production or aggregation of proteins specifically implicated in diverse diseases (or promoting their elimination) or of inhibiting the production or action of free radicals in the nervous system. The former should target one of these various diseases, and the latter should act on a wide range of diseases. The two approaches may conceivably be combined.

Aging↗
PubMed2001

The evolution of controlled multitasked gene networks: the role of introns and other noncoding RNAs in the development of complex organisms.

Eukaryotic phenotypic diversity arises from multitasking of a core proteome of limited size. Multitasking is routine in computers, as well as in other sophisticated information systems, and requires multiple inputs and outputs to control and integrate network activity. Higher eukaryotes have a mosaic gene structure with a dual output, mRNA (protein-coding) sequences and introns, which are released from the pre-mRNA by posttranscriptional processing. Introns have been enormously successful as a class of sequences and comprise up to 95% of the primary transcripts of protein-coding genes in mammals. In addition, many other transcripts (perhaps more than half) do not encode proteins at all, but appear both to be developmentally regulated and to have genetic function. We suggest that these RNAs (eRNAs) have evolved to function as endogenous network control molecules which enable direct gene-gene communication and multitasking of eukaryotic genomes. Analysis of a range of complex genetic phenomena in which RNA is involved or implicated, including co-suppression, transgene silencing, RNA interference, imprinting, methylation, and transvection, suggests that a higher-order regulatory system based on RNA signals operates in the higher eukaryotes and involves chromatin remodeling as well as other RNA-DNA, RNA-RNA, and RNA-protein interactions. The evolution of densely connected gene networks would be expected to result in a relatively stable core proteome due to the multiple reuse of components, implying that cellular differentiation and phenotypic variation in the higher eukaryotes results primarily from variation in the control architecture. Thus, network integration and multitasking using trans-acting RNA molecules produced in parallel with protein-coding sequences may underpin both the evolution of developmentally sophisticated multicellular organisms and the rapid expansion of phenotypic complexity into uncontested environments such as those initiated in the Cambrian radiation and those seen after major extinction events.

Animals↗
PubMed1996

A molecular clock based on the expansion of gene families.

There is evidence to suggest that eukaryotic genomes are subject to frequent insertions and deletions of non-coding DNA. This may lead to a gradual increase or decrease in genome size, or to a dynamic equilibrium in which the overall size remains constant. We argue, however, that there is a bias favouring an accumulation of non-coding DNA in the proximity of genes. Such bias causes a progressive change in genome structure regardless of whether the overall genome size increases, decreases or remains constant. We show that this change may serve as a 'molecular clock', supplementing that provided by nucleotide substitution rates.

Animals↗
PubMed2005

Estimating a nucleotide substitution rate for maize from polymorphism at a major domestication locus.

To estimate a rate for single nucleotide substitutions for maize (Zea mays ssp. mays), we have taken advantage of data from genetic and archaeological studies of the domestication of maize from its wild ancestor, teosinte (Z. mays ssp. parviglumis). Genetic studies have shown that the teosinte branched1 (tb1) gene was a major target of human selection during maize domestication, and sequence diversity in the intergenic region 5' to the tb1-coding sequence is extraordinarily low. We show that polymorphism in this region is consistent with new mutation following fixation for a small number of tb1 haplotypes during domestication. Archeological studies suggest that maize was domesticated approximately 6,250-10,000 years ago and subsequently the size of the maize population is thought to have expanded rapidly. Using the observed number of mutations within the region of selection at tb1, the approximate age of maize domestication, and approximations for the maize genealogy, we have derived estimates for the nucleotide substitution rate for the tb1 intergenic region. Using two approaches, one of which is a coalescent approach, we obtain rate estimates of approximately 2.9 x 10(-8) and 3.3 x 10(-8) substitutions per site per year. We also show that the pattern of polymorphism in the tb1 intergenic region appears to have been strongly affected by the mutagenic effect of DNA methylation. Excluding target sites of symmetric DNA methylation (CG and CNG sites) from analysis, the mutation rate estimates are reduced by approximately 50%-60%, while the rates for CG and CNG sites are nearly an order of magnitude higher. We use rate estimates from the tb1 region to estimate the timing of expansion of transposable elements in the maize genome and suggest that this expansion occurred primarily within the last million years.

Base Sequence↗
PubMed2000

Developmental patterns of chromatin structure and DNA methylation responsible for epigenetic expression of a maize regulatory gene.

Epigenetic regulatory mechanisms heritably alter patterns of gene expression without changes in DNA sequence. Epigenetic states are often correlated with developmentally imposed alterations in genomic DNA methylation and local chromatin structure. Pl-Blotched is a stable epigenetic allele of the maize anthocyanin regulatory gene, purple plant1(pl). Pl-Blotched plants display a variegated pattern of pigmentation that contrasts sharply with the uniformly dark purple pigmentation of plants carrying the dominant Pl-Rhoades allele. Previously, we showed that the lower level of pigmentation in Pl-Blotched is correlated with lower pl mRNA levels and increased DNA methylation at some sites. To explore how DNA methylation, chromatin structure, and developmental stage might contribute to the expression of Pl-Blotched, we used methylation-sensitive restriction enzymes and DNaseI sensitivity assays to compare the methylation status and chromatin structure of Pl-Blotched and Pl-Rhoades at different stages in development. Both alleles exhibit developmentally sensitive changes in methylation. In Pl-Blotched, methylation of two diagnostic HpaII/MspI sites increases progressively, coincident with the juvenile-to-adult transition in growth. In seedlings, the chromatin encompassing the coding region of the gene is less sensitive to DNaseI digestion in Pl-Blotched than in Pl-Rhoades. Developmental maturation from seedling to adult is accompanied by expansion of this closed chromatin domain to include the promoter and downstream flanking sequences. We provide evidence to show that chromatin structure, rather than DNA methylation, is the primary epigenetic determinant for the phenotypic differences between Pl-Blotched and Pl-Rhoades.

Alleles↗
PubMed1993

Genes with triplet repeats: candidate mediators of neuropsychiatric disorders.

Recently a new form of human mutation-expansion of trinucleotide repeats-has been found to cause the diseases of fragile X syndrome, spinal and bulbar muscular atrophy, myotonic dystrophy and, most recently, Huntington's disease. We review the emerging data on the genetics and neurobiology of these disorders. Three are characterized by unusual patterns of inheritance, in particular, genetic 'anticipation', in which the severity of the disorder increases and the age of onset decreases in successive generations of a pedigree. Several idiopathic neuropsychiatric disorders have features of inheritance consistent with anticipation. In bipolar affective disorder, there is evidence for both earlier age of onset and more severe illness in the second generation of a subset of unilineal pedigrees. There is also the suggestion of anticipation in some forms of schizophrenia, spinocerebellar atrophy and autism. Triplet repeats are present in additional known genes, both in coding regions and untranslated regions. Furthermore, many novel genes with triplet repeats are expressed in the human brain, and these are candidates to cause some forms of these neuropsychiatric disorders.

Humans↗
PubMed2002

Dominantly inherited, non-coding microsatellite expansion disorders.

Dominantly inherited diseases are generally caused by mutations resulting in gain of function protein alterations. However, a CTG expansion located in the 3' untranslated portion of a kinase gene was found to cause myotonic dystrophy type 1, a multisystemic dominantly inherited disorder. The recent discovery that an untranslated CCTG expansion causes the same constellation of clinical features in myotonic dystrophy type 2 (DM2), along with other recent discoveries on DM1 pathogenesis, have led to the understanding that both DM1 and DM2 mutations are pathogenic at the RNA level. These findings indicate the existence of a new category of disease wherein repeat expansions in RNA alter cellular function. Pathogenic repeat expansions in RNA may also be involved in spinocerebellar ataxia types 8, 10 and 12, and Huntington's disease-like type 2.

Genes, Dominant↗
PubMed2003

MECP2 mutations or polymorphisms in mentally retarded boys: diagnostic implications.

BACKGROUND: Among the well characterized X-linked conditions causing mental retardation, mutations in the methyl-CpG-binding protein 2 gene (MECP2) in Xq28 have been found in up to 85% of patients with Rett syndrome, a neurologic disorder which, in addition to other symptoms, severely affects higher cognitive functions in females. Mutations in the MECP2 gene are involved in a broad spectrum of phenotypes from classical Rett syndrome to mild intellectual difficulties in females and neonatal encephalopathy in males. Recently, mutations in the MECP2 gene were reported in males with non-specific mental retardation suggesting that defects in MECP2 could be responsible for up to 2% of X-linked mental retardation. METHODS: We screened by denaturing high-pressure liquid chromatography the entire coding region and flanking intronic sequences of the MECP2 gene in a cohort of 354 mentally retarded males found negative for an expansion across the FRAXA CGG repeat and in a family in which a boy and his sister were mentally retarded. RESULTS: We identified mainly silent polymorphisms within the MECP2 gene, together with four sequence alterations of unknown significance, i.e. three missense mutations (T197M, T228S, and P376S) and one substitution at position -19 in intron 3 (378-19delT). Further familial investigations allowed us to ruled out a pathogenic effect for the intronic variant, the T228S and the P376S missense mutations. CONCLUSIONS: These results confirm that MECP2 mutations in males are far more rare than initially thought and call for a careful evaluation of the pathogenicity of the MECP2 missense mutations identified in mentally retarded males before genetic counseling is proposed to the relatives.

Chromatography, High Pressure Liquid↗
PubMed2003

Language-tree divergence times support the Anatolian theory of Indo-European origin.

Languages, like genes, provide vital clues about human history. The origin of the Indo-European language family is "the most intensively studied, yet still most recalcitrant, problem of historical linguistics". Numerous genetic studies of Indo-European origins have also produced inconclusive results. Here we analyse linguistic data using computational methods derived from evolutionary biology. We test two theories of Indo-European origin: the 'Kurgan expansion' and the 'Anatolian farming' hypotheses. The Kurgan theory centres on possible archaeological evidence for an expansion into Europe and the Near East by Kurgan horsemen beginning in the sixth millennium BP. In contrast, the Anatolian theory claims that Indo-European languages expanded with the spread of agriculture from Anatolia around 8,000-9,500 years bp. In striking agreement with the Anatolian hypothesis, our analysis of a matrix of 87 languages with 2,449 lexical items produced an estimated age range for the initial Indo-European divergence of between 7,800 and 9,800 years bp. These results were robust to changes in coding procedures, calibration points, rooting of the trees and priors in the bayesian analysis.

Agriculture↗
PubMed2006

Nucleotide sequence analyses of the MRP1 gene in four populations suggest negative selection on its coding region.

BACKGROUND: The MRP1 gene encodes the 190 kDa multidrug resistance-associated protein 1 (MRP1/ABCC1) and effluxes diverse drugs and xenobiotics. Sequence variations within this gene might account for differences in drug response in different individuals. To facilitate association studies of this gene with diseases and/or drug response, exons and flanking introns of MRP1 were screened for polymorphisms in 142 DNA samples from four different populations. RESULTS: Seventy-one polymorphisms, including 60 biallelic single nucleotide polymorphisms (SNPs), ten insertions/deletions (indel) and one short tandem repeat (STR) were identified. Thirty-four of these polymorphisms have not been previously reported. Interestingly, the STR polymorphism at the 5' untranslated region (5'UTR) occurs at high but different frequencies in the different populations. Frequencies of common polymorphisms in our populations were comparable to those of similar populations in HAPMAP or Perlegen. Nucleotide diversity indices indicated that the coding region of MRP1 may have undergone negative selection or recent population expansion. SNPs E10/1299 G>T (R433S) and E16/2012 G>T (G671V) which occur at low frequency in only one or two of four populations examined were predicted to be functionally deleterious and hence are likely to be under negative selection. CONCLUSION: Through in silico approaches, we identified two rare SNPs that are potentially negatively selected. These SNPs may be useful for studies associating this gene with rare events including adverse drug reactions.

Databases, Genetic↗