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PubMed2003

[Study on the evolutionary pressure on the env gene of the human immunodeficiency virus type 1 CRF01-AE strains circulating in China].

OBJECTIVE: To identify variations in the env gene of human immunodeficiency virus type 1 (HIV-1) subtype CRF01-AE strains circulating in China and to elucidate the potential relationship between genetic variation and evolutionary pressure. METHODS: Fragments of the HIV-1 env gene were amplified by nested-polymerase chain reaction (n-PCR) from the whole blood of HIV-1 infected individuals from four provinces in Southeast China (Guangdong, Hunan, Jiangsu and Jiangxi). The PCR products were then directly sequenced by ABI 377 DNA sequencers. The sequences covering the env V3-V4 region of 34 HIV-1 subtype CRF01-AE strains were selected to analyse phylogenetic trees and amino acid mutations. The accumulation of synonymous (Ks) and antonymous (Ka) substitutions as well as Ks/Ka ratios were calculated using DIVERGE. RESULTS: Phylogenetic trees showed that the 34 HIV-1 subtype CRF01-AE strains from China clustered with the Chinese AE reference strain (AE.97CNGX2F), as well as with the reference strains from Thailand (AE.CM240 and AE.93TH253). The amino acid sequences of the env V4 and C3 regions in the samples were highly variable, compared with those of V3 and V3-downstream regions. The V3 loop central motif in the majority (87.5%) of the strains was GPGQ. The majority of strains did not contain positively charged amino acids at positions 306 and 320 in V3 loop. The N-linked glycosylation sites in the V3-V4 region and flanking regions in these strains were relatively conserved. Analysis of the entire region showed that the mean Ks values were significantly higher than that of the Ka values (P < 0.001), with the Ks/Ka significantly higher than 1.0 (P < 0.001). In contrast, the Ks/Ka ratio in the V4 region was significantly lower than 1.0 (P < 0.01). CONCLUSIONS: Our study indicated that the majority of HIV-1 subtype CRF01-AE strains circulating in China were highly homogeneous. The amino acid sequences of the V4 and C3 regions were significantly more variable than those of the V3 loop. Our analysis also suggested that the phenotype of nearly all strains was likely to be non-syncytium inducing (NSI). Finally, the variation found in the V3-V4 sequence was significantly influenced by functional constraints as opposed to positive selective pressure, while the variability of the lone V4 region was strongly related to positive selective pressure.

Adult↗
PubMed1984

Comparison of Bacillus subtilis phages PZA, phi 29 and phi 15.

Morphologically identical phages PZA, PZE , phi 29, and phi 15 can be distinguished by the neutralization test with rabbit antisera and by host range specificity. Each member of this phage group contains 18 kb double-stranded linear DNA carrying proteins covalently attached to its 5' ends. Physical maps of their DNA constructed with the use of restriction endonucleases EcoRI, HpaI, HindIII, BspRI, and XbaI and DNA-DNA hybridization experiments show a closer relationship between phi 29 and PZE than between phi 29 and phi 15 or phi 29 and PZA. phi 15 is closer to PZA than to phi 29. This conclusion is supported by analysis of differential denaturation profiles of the phage DNAs. Sequencing of selected parts of phi 29 and PZA DNAs reveals 93% homology with a preference for synonymous base replacements (silent mutations) randomly distributed in the coding regions. Using promoter-probe plasmid pPV33 -H the region functioning as a promoter in E. coli was localized on the smallest EcoRI fragment of PZA and phi 29 DNAs. Comparison of the nucleotide sequence of this region with known promoters of B. subtilis shows extensive homologies with at least two types of promoters of different specificities, namely those recognized by factors sigma 28 of B. subtilis and sigma gp28 of phage SPO1 . These promoter-like regions overlap and the whole sequence is conserved in both phages.

Bacillus subtilis↗
PubMed1988

Directional mutation pressure and transfer RNA in choice of the third nucleotide of synonymous two-codon sets.

Bacterial species have diverged into a series of families, some with high G + C content in their DNA, and other with high A + T content, resulting, respectively, from G.C- and A.T-directional mutation pressures. Such mutation pressure (G.C/A.T pressure) may be an important determinant for codon usage. It has also been suggested that tRNA acts as a selective constraint for determining codon usage. We have studied the relation between G.C/A.T pressure and tRNA constraints in determining choice of the third nucleotide of eight two-codon sets, using codon usage data obtained from protein genes in four bacterial species, Mycoplasma capricolum, Bacillus subtilis, Escherichia coli, and Micrococcus luteus, and in liverwort (Marchantia polymorpha) chloroplasts. The genomic G + C contents of these range from 25% to 74%. The results demonstrate that tRNA levels act additively to A.T and G.C pressure in affecting contents of A (pairing with *UNN anticodons, in which *U indicates a 2-thiouridine derivative) and C (pairing with GNN anticodons) or G (pairing with CNN anticodons), respectively, in third nucleotide positions of codons.

Chloroplasts↗
PubMed2005

Exclusion of non-synonymous SNPs and a polyglutamine tract in SMRT/N-CoR2 as common deleterious mutation for bipolar disorder in the Sagnenay-Lac-St-Jean population.

Bipolar disorder (BP) is a psychiatric illness with both genetic and environmental components occurring with a prevalence of slightly more than 1%. Our previous linkage and case/control studies have pointed to a susceptibility locus for BP in the 12q24.31 chromosomal region. Here, we investigated the possible involvement of the SMRT/N-CoR2 gene, which encodes for the nuclear receptor co-repressor 2. SMRT/N-CoR2 was retained as a candidate gene for BP because of its location within our candidate gene region and its interactions with thyroid hormone receptors. We screened SMRT/N-CoR2 for the presence of polymorphism/mutation in coding sequences and exon-intron junctions. Four non-synonymous SNPs and a polyglutamine tract (CAG repeat) in the coding exon 14 were analyzed in a case/control sample from the Saguenay-Lac-St-Jean (SLSJ) area of Quebec (213 cases and 214 controls). Our data indicated no significant allelic/genotypic association between any of the five mutations and bipolar phenotype when they were considered either individually or as haplotypes. Finally, the CAG repeat observed in SMRT/N-CoR2 did not demonstrate allelic instability and consequently it is unlikely that this polymorphism could be involved in the anticipation phenomenon reported for BP.

Alleles↗
PubMed2005

Reduced genetic variation occurs among genes of the highly clonal plant pathogen Xanthomonas axonopodis pv. vesicatoria, including the effector gene avrBs2.

The bacterial plant pathogen Xanthomonas axonopodis pv. vesicatoria, also known as Xanthomonas campestris pv. vesicatoria group A, is the causal agent of bacterial spot in pepper and tomato. In order to test different models that may explain the coevolution of avrBs2 with its host plants, we sequenced avrBs2 and six chromosomal loci (total of 5.5 kb per strain) from a global sample of 55 X. axonopodis pv. vesicatoria strains collected from diseased peppers. We found an extreme lack of genetic variation among all X. axonopodis pv. vesicatoria genomic loci (average nucleotide diversity, pi = 9.1 x 10(-5)), including avrBs2. This lack of diversity is consistent with X. axonopodis pv. vesicatoria having undergone a recent population bottleneck and/or selective sweep followed by population expansion. Coalescent analysis determined that approximately 1.4 x 10(4) to 7.16 x 10(4) bacterial generations have passed since the most recent common ancestor (MRCA) of the current X. axonopodis pv. vesicatoria population. Assuming a range of 50 to 500 bacterial generations per year, only 28 to 1,432 years have passed since the MRCA. This time frame coincides with human intervention with the pathogen's host plants, from domestication to modern agricultural practices. Examination of 19 mutated (loss-of-function) avrBs2 alleles detected nine classes of mutations. All mutations affected protein coding, while no synonymous changes were found. The nature of at least one of the avrBs2 mutations suggests that it may be possible to observe one stage of an evolutionary arms race as X. axonopodis pv. vesicatoria responds to selection pressure to alter avrBs2 to escape host plant resistance.

Alleles↗
PubMed2002

Hill-Robertson interference is a minor determinant of variations in codon bias across Drosophila melanogaster and Caenorhabditis elegans genomes.

According to population genetics models, genomic regions with lower crossing-over rates are expected to experience less effective selection because of Hill-Robertson interference (HRi). The effect of genetic linkage is thought to be particularly important for a selection of weak intensity such as selection affecting codon usage. Consistent with this model, codon bias correlates positively with recombination rate in Drosophila melanogaster and Caenorhabditis elegans. However, in these species, the G+C content of both noncoding DNA and synonymous sites correlates positively with recombination, which suggests that mutation patterns and recombination are associated. To remove this effect of mutation patterns on codon bias, we used the synonymous sites of lowly expressed genes that are expected to be effectively neutral sites. We measured the differences between codon biases of highly expressed genes and their lowly expressed neighbors. In D. melanogaster we find that HRi weakly reduces selection on codon usage of genes located in regions of very low recombination; but these genes only comprise 4% of the total. In C. elegans we do not find any evidence for the effect of recombination on selection for codon bias. Computer simulations indicate that HRi poorly enhances codon bias if the local recombination rate is greater than the mutation rate. This prediction of the model is consistent with our data and with the current estimate of the mutation rate in D. melanogaster. The case of C. elegans, which is highly self-fertilizing, is discussed. Our results suggest that HRi is a minor determinant of variations in codon bias across the genome.

Animals↗
PubMed2002

The functional importance of disease-associated mutation.

BACKGROUND: For many years, scientists believed that point mutations in genes are the genetic switches for somatic and inherited diseases such as cystic fibrosis, phenylketonuria and cancer. Some of these mutations likely alter a protein's function in a manner that is deleterious, and they should occur in functionally important regions of the protein products of genes. Here we show that disease-associated mutations occur in regions of genes that are conserved, and can identify likely disease-causing mutations. RESULTS: To show this, we have determined conservation patterns for 6185 non-synonymous and heritable disease-associated mutations in 231 genes. We define a parameter, the conservation ratio, as the ratio of average negative entropy of analyzable positions with reported mutations to that of every analyzable position in the gene sequence. We found that 84.0% of the 231 genes have conservation ratios less than one. 139 genes had eleven or more analyzable mutations and 88.0% of those had conservation ratios less than one. CONCLUSIONS: These results indicate that phylogenetic information is a powerful tool for the study of disease-associated mutations. Our alignments and analysis has been made available as part of the database at http://cancer.stanford.edu/mut-paper/. Within this dataset, each position is annotated with the analysis, so the most likely disease-causing mutations can be identified.

Computational Biology↗
PubMed1998

Somatic hypermutation of the new antigen receptor gene (NAR) in the nurse shark does not generate the repertoire: possible role in antigen-driven reactions in the absence of germinal centers.

The new antigen receptor (NAR) gene in the nurse shark diversifies extensively by somatic hypermutation. It is not known, however, whether NAR somatic hypermutation generates the primary repertoire (like in the sheep) or rather is used in antigen-driven immune responses. To address this issue, the sequences of NAR transmembrane (Tm) and secretory (Sec) forms, presumed to represent the primary and secondary repertoires, respectively, were examined from the peripheral blood lymphocytes of three adult nurse sharks. More than 40% of the Sec clones but fewer than 11% of Tm clones contained five mutations or more. Furthermore, more than 75% of the Tm clones had few or no mutations. Mutations in the Sec clones occurred mostly in the complementarity-determining regions (CDR) with a significant bias toward replacement substitutions in CDR1; in Tm clones there was no significant bias toward replacements and only a low level of targeting to the CDRs. Unlike the Tm clones where the replacement mutational pattern was similar to that seen for synonymous changes, Sec replacements displayed a distinct pattern of mutations. The types of mutations in NAR were similar to those found in mouse Ig genes rather than to the unusual pattern reported for shark and Xenopus Ig. Finally, an oligoclonal family of Sec clones revealed a striking trend toward acquisition of glutamic/aspartic acid, suggesting some degree of selection. These data strongly suggest that hypermutation of NAR does not generate the repertoire, but instead is involved in antigen-driven immune responses.

Amino Acid Sequence↗
PubMed2006

Mitochondrial DNA mutations in renal cell carcinomas revealed no general impact on energy metabolism.

Previously, renal cell carcinoma tissues were reported to display a marked reduction of components of the respiratory chain. To elucidate a possible relationship between tumourigenesis and alterations of oxidative phosphorylation, we screened for mutations of the mitochondrial DNA (mtDNA) in renal carcinoma tissues and patient-matched normal kidney cortex. Seven of the 15 samples investigated revealed at least one somatic heteroplasmic mutation as determined by denaturating HPLC analysis (DHPLC). No homoplasmic somatic mutations were observed. Actually, half of the mutations presented a level of heteroplasmy below 25%, which could be easily overlooked by automated sequence analysis. The somatic mutations included four known D-loop mutations, four so far unreported mutations in ribosomal genes, one synonymous change in the ND4 gene and four nonsynonymous base changes in the ND2, COI, ND5 and ND4L genes. One renal cell carcinoma tissue showed a somatic A3243G mutation, which is a known frequent cause of MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episode) and specific compensatory alterations of enzyme activities of the respiratory chain in the tumour tissue. No difference between histopathology and clinical progression compared to the other tumour tissues was observed. In conclusion, the low abundance as well as the frequently observed low level of heteroplasmy of somatic mtDNA mutations indicates that the decreased aerobic energy capacity in tumour tissue seems to be mediated by a general nuclear regulated mechanism.

Base Sequence↗
PubMed2006

Genetic mutation screening in an italian cohort of nonsyndromic pheochromocytoma/paraganglioma patients.

To assess the prevalence of genetic mutations in nonsyndromic pheochromocytoma/paraganglioma (PHEO/PGL) patients we have performed a systematic search for mutations in the succinate dehydrogenase (SDH) B, C, and D subunits, von Hippel-Lindau (VHL), and RET genes by direct bidirectional sequencing. Patients were selected from the medical records of hypertension centers. After exclusion of syndromic patients, 45 patients with familial (F+, n=3) and sporadic (F-, n=42) cases of isolated PHEO/PGL were considered. They included 35 patients with PHEO, 7 with PGL, and 3 with head/neck PGL (hnPGL). Three patients with PHEO (2F-, 1F+) presented VHL mutations (P86A, G93C, and R167W), six with PGL (4F-, 2F+) were positive for SDH or VHL mutations (SDHB R230G in two patients, SDHB S8F, R46Q, R90Q, and VHL P81L in one subject each), and one with hnPGL carried the SDHD 348-351delGACT mutation. We have also detected missense (SDHB S163P, SDHD H50R and G12S), synonymous (SDHB A6A, SDHD S68S), and intronic mutations that have been considered nonpathological polymorphic variants. No mutation was found in SDHC or RET genes. Our data indicate that germline mutations of VHL and SDH subunits are not infrequent in familial as well as in sporadic cases of nonsyndromic PHEO/PGL (overall, 12 of 45 probands, 22%). Accordingly, screening for such mutations seems to be justified. However, a more precise characterization of the functional relevance of any observed sequence variant and of other genetic and environmental determinants of neoplastic transformation is essential in order to plan appropriate protocols for family screening and follow-up.

Adrenal Gland Neoplasms↗
PubMed1997

Role of random genetic drift in the evolution of interactive systems.

Through comparative studies of DNA sequences it has become possible to test the neutral and the selection theories of molecular evolution. The separate estimation of the numbers of synonymous and non-synonymous substitutions is one of the most powerful tools for detecting selection. The patterns on the average and variance of these two types of substitutions of mammalian genes turned out to be in accord with the slightly deleterious or the nearly neutral mutation theory for non-synonymous changes. Interactive systems at the amino acid level were suggested to be responsible for such nearly neutral or very weak selection. An attractive model is the NK model of Kauffman, which assumes that each amino acid makes a fitness contribution that depends upon the amino acid and upon K other amino acids among the N that make the protein. It is known that the fitness landscape is very rugged for K > or = 2. Population genetic analysis of this model suggest that protein evolution obeys the nearly neutral theory and that random genetic drift is important. In other words, evolution becomes rapid in small populations because proportion of near-neutrality increases among new mutations, and proteins as interactive systems evolve by shifting through random genetic drift on the multipeaked fitness landscape.

Animals↗
PubMed2005

Combined monogenic hypercholesterolemia and hypoalphalipoproteinemia caused by mutations in LDL-R and LCAT genes.

We studied a three generation family with co-dominant monogenic hypercholesterolemia and hypoalphalipoproteinemia. The proband, a 48 year-old male, was found to be heterozygous for a previously reported mutation in LDL receptor (LDL-R) gene (IVS15-3 c>a) and a novel mutation in exon 6 of lecithin cholesterol acyltransferase (LCAT) gene (c.803 G>A) causing a non-synonymous amino acid substitution (p.R244H). These mutations segregated independently in the family. The LDL-R mutation was associated with high levels of LDL-C (6.20-9.85 mmol/L) and apo B (170-255 mg/dL), comparable to those previously reported in carriers of the same mutation. The LCAT mutation was associated with low levels of HDL-C (0.67-0.80 mmol/L) and apo A-I (96-110 mg/dL). The proband had reduced LCAT function, as measured by cholesterol esterification rate (29 nmol/(mL/h) versus 30-60 nmol/(mL/h)), LCAT activity (10 nmol/(mL/h) versus 20-55 nmol/(mL/h)) and LCAT mass (2.87 microg/mL versus 3.1-6.7 microg/mL). Carriers of LCAT mutation had lower LCAT activity and a tendency to reduced cholesterol esterification rate (CER) and LCAT mass as compared to non-carrier family members. The LCAT mutation was not found in 80 control subjects and 60 patients with primary hypoalphalipoproteinemia. Despite the unfavourable lipoprotein profile, the proband had only mild clinical signs of atherosclerosis. This unexpected finding is probably due to the intensive lipid lowering treatment the patient has been on over the last decade.

Adolescent↗
PubMed2005

A highly unexpected strong correlation between fixation probability of nonsynonymous mutations and mutation rate.

Under prevailing theories, the nonsynonymous-to-synonymous substitution ratio (i.e. K(a)/K(s)), which measures the fixation probability of nonsynonymous mutations, is correlated with the strength of selection. In this article, we report that K(a)/K(s) is also strongly correlated with the mutation rate as measured by K(s), and that this correlation appears to have a similar magnitude as the correlation between K(a)/K(s) and selective strength. This finding cannot be reconciled with current theories. It suggests that we should re-evaluate the current paradigms of coding-sequence evolution, and that the wide use of K(a)/K(s) as a measure of selective strength needs reassessment.

Animals↗
PubMed1993

Unbiased estimation of the rates of synonymous and nonsynonymous substitution.

The current convention in estimating the number of substitutions per synonymous site (KS) and per nonsynonymous site (KA) between two protein-coding genes is to count each twofold degenerate site as one-third synonymous and two-thirds nonsynonymous because one of the three possible changes at such a site is synonymous and the other two are nonsynonymous. This counting rule can considerably overestimate the KS value because transitional mutations tend to occur more often than transversional mutations and because most transitional mutations at twofold degenerate sites are synonymous. A new method that gives unbiased estimates is proposed. An application of the new and the old method to 14 pairs of mouse and rat genes shows that the new method gives a KS value very close to the number of substitutions per four-fold degenerate site whereas the old method gives a value 30% higher. Both methods give a KA value close to the number of substitutions per nondegenerate site.

Animals↗
PubMed2006

Modeling and analyzing three-dimensional structures of human disease proteins.

Three-dimensional structures of proteins, experimental or predicted, show us how these molecular machines actually work. With the help of information on disease-related mutations, they can also show us how they malfunction in diseases. Such understanding, currently lacking for most human diseases, is an important first step before designing drugs or therapies to cure specific diseases. Here we used homology modeling to model human disease-related proteins, and studied structural characteristics of disease related mutations and compared them with non synonymous SNPs. 1484 domains from 874 proteins were modeled, and together with experimentally determined structures of 369 domains they provided the structural coverage of 48% of total residues in 1237 human disease proteins. We found that disease-related mutations have statistically significantly preference to form clusters on protein surfaces. In contrast, the non-synonymous SNPs appear to be randomly distributed on the surface. We interpret these results as an indication that disease mutations affect protein-protein interaction interfaces. This interpretation is supported by the analysis of 8 experimentally determined complexes between disease proteins, where disease-related mutations are clearly located in the binding interface of proteins, while SNPs are not. The non-uniform distribution of disease mutations indicates that we can use this feature as guidance in modeling and evaluating human disease proteins and their complexes. We set up a resource for Disease Protein Models (DPM at http://ffas.burnham.org/DPM), which can be used for studying the relation between disease and mutation/polymorphism sites in the context of protein 3D structures and complexes.

Computational Biology↗
PubMed2005

High frequency somatic mutations in RASSF1A in nasopharyngeal carcinoma.

High frequency loss of 3p21.3 region is a common event in various kinds of tumors including nasopharyngeal carcinoma (NPC). RASSF1A has been identified as a putative tumor suppressor gene residing in this region. Chromosome alterations and epigenetic changes are commonly observed as mechanisms for inactivation of RASSF1A function. In this study, we applied the PCR-cloning-sequencing strategy to examine somatic mutations in RASSF1A in NPC tissues as compared with the sequences detected in the matched peripheral blood lymphocytes. Our results revealed a high incidence of RASSF1A mutation in primary tumor tissues of NPC. There are totally 35 mutations identified in 74% (17/23) of these NPC cases, including 30 transitions, three transversions and two deletions. Most of these mutations result in amino acid changes: three nonsense (stop codon) mutations, two-1 bp deletion (frameshift), 26 missense and the remaining four are synonymous (silent). No obvious 'hot-spot' mutations were observed in this study. A similarly high rate (74%) of promoter methylation of RASSF1A was also detected in the same group of NPC tissues, but no significant correlation between mutation and methylation was detected. Our results suggest various mechanisms involved in inactivation of RASSF1A function and indicate a critical role of RASSF1A in NPC development.

Adult↗
PubMed2004

Synonymous genetic polymorphisms within Brazilian human immunodeficiency virus Type 1 subtypes may influence mutational routes to drug resistance.

BACKGROUND: Most published data on antiretroviral-drug resistance is generated from in vitro or in vivo studies of subtype B virus. However, this subtype is associated with <10% of HIV infections worldwide, and it is essential to explore subtype-specific determinants of drug resistance. One potential cause of the differences between subtypes is the synonymous codon usage at key resistance positions. METHODS: We investigated the nucleotide sequences at drug resistance-related sites, for all major Brazilian subtypes (B, C, and F1) of human immunodeficiency virus type 1 (HIV-1) group M. RESULTS: We identified a change at positions 151 and 210 of the reverse-transcriptase region in subtype F1, such that the emergence of these key nucleoside/nucleotide analogue resistance mutations required an extra nucleotide change in subtype F1, compared with subtypes B and C. The clinical significance of position 210 was confirmed within a large Brazilian database, in which we identified a lower prevalence of the L210W mutation in subtype F1 virus, compared with subtype B virus, in patients matched for thymidine-analogue experience. An inverse relationship between the L210W and K70R mutations was also observed. CONCLUSIONS: The findings of the present study illustrate an important mechanism by which a subtype may determine genetic routes to resistance, with implications for treatment strategies for populations infected with HIV-1 subtype F.

Base Sequence↗
PubMed2006

Maternal polymorphisms 677C-T and 1298A-C of MTHFR, and 66A-G MTRR genes: is there any relationship between polymorphisms of the folate pathway, maternal homocysteine levels, and the risk for having a child with Down syndrome?

This study was aimed at analyzing the effect of mutations in three non-synonymous SNP genes (677C > T and 1298A > C of the methylenetetrahydrofolate reductase (MTHFR) gene, and 66A > G in the MTRR gene) on total plasmatic homocysteine (Hcy), in 91 mothers of Down syndrome (DS) infants and 90 control mothers. The comparison of both groups of mothers is a new way to determine if those mutations and their interactions increase the risk for DS. Material came from the case-control network of the Spanish Collaborative Study of Congenital Malformations (ECEMC). Using a general lineal model in a backwards step, we performed the analyses including the different mutations, maternal age, the fact that each mother had a DS or a control infant, and all possible interactions of these variables, in the models, being maternal Hcy the continuous dependent variable. In another model, maternal folic acid intake during the third trimester of pregnancy was added. The results from both models were essentially the same: Hcy levels variability differs from case mothers to control ones, the presence of the MTHFR1298A > C polymorphism also affects significantly the Hcy variance, as it does the statistical interaction between the mutations MTRR66A > G and MTHFR1298A > C in the mother. In this sense, the interaction between different polymorphisms may totally modify their individual effects, and some of those effects are different in mothers of DS children and in controls' mothers. For instance, only two mutations in MTRR66 (GGAA) in mothers of control infants increase the reference maternal Hcy level in 4.66 units, and the individual effect of the genotype with only two mutations in the MTHFR1298 gene (AACC) increases the reference Hcy level in 12.74 units. However, the presence of the four mutations (GGCC) interacts giving a statistically significant decrease in 6.00 units in the level of Hcy in control mothers. On the contrary, in mothers of DS infants, the sole presence of two mutations in one of these two genes decreases the levels of Hcy (-2.31 units for GGAA genotype, and -3.43 units for AACC genotype), while the presence of the four mutations (GGCC) increases Hcy in 9.53 units. Taking into consideration that in the one-carbon metabolism cystathionine beta-synthase (CBS) catalyzes Hcy in an irreversible way, and that CBS gene is located in chromosome 21, fetuses and infants with DS have functional folate deficiency due to overexpression of CBS. This fact, as well as others influencing Hcy levels (such as nutrients interactions and lifestyle), together with the fetal genotype, suggest that their relationship with DS could be through an effect on fetal survival up to birth. Three possible mechanisms are considered by evaluating the results in the light of the present knowledge on cytology and molecular biology.

Case-Control Studies↗