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At least 775 records · Page 43Linked to original sources
PubMed2006

QTL-specific genotype-by-smoking interaction and burden of calcified coronary atherosclerosis: the NHLBI Family Heart Study.

BACKGROUND: Calcified coronary plaque (CCP) is a complex trait influenced by both genes and environment, and plausibly an interaction between the two. Because the familial aggregation of CCP has been demonstrated and smoking is a significant, independent predictor of CCP, we assessed the evidence for genotype-by-smoking interaction and conducted linkage analysis of quantitative Agatston CCP scores in participants of the NHLBI Family Heart Study (FHS). METHODS: During standardized clinical exams smoking habits were ascertained and CCP was quantified with cardiac computed tomography (CT). Among 4387 relationship pairs from 2128 Caucasian examinees variance component analysis was implemented in SOLAR to examine: (1) additive genotype-by-smoking status interaction using a variance component approach; (2) linkage analysis in the full sample and among smoking subsets defined by individual smoking exposure; (3) QTL-specific genotype-by-smoking interaction in the regions that appeared to differentiate between smoking strata. RESULTS: The prevalence of CCP (and median Agatston score) was 75% (184.6) in men and 48% (51.0) in women. We detected four genome-wide significant logarithm of odds (LOD) scores in samples stratified by individual smoking exposure: chromosome 4 at 122cM (nearest marker D4S2297; robust adjusted LOD=3.1; q=0.053), chromosome 6 at 99cM (nearest marker D6S1056; robust adjusted LOD=3.3; q=0.053), chromosome 11 at 19cM (nearest marker D11S199; robust adjusted LOD=4.0; q=0.02) and chromosome 13 at 77cM (nearest marker D13S892; robust adjusted LOD=3.1; q=0.053). Additive and QTL-specific genotype-by-smoking interaction was detected on chromosomes 4, 6, 11 and 13; all P<0.05. Three of the four QTLs identified in this report have been previously linked to atherosclerosis and harbor interesting candidate genes. CONCLUSIONS: These findings demonstrate the importance of considering complex interactions in the search for genes that influence the pathogenesis of CCP.

Adult↗
PubMed2006

Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus.

Autoantibodies are clinically relevant biomarkers for numerous autoimmune disorders. The genetic basis of autoantibody production in systemic lupus erythematosus (SLE) and other autoimmune diseases is poorly understood. In this study, we characterized autoantibody profiles in 1,506 individuals from 229 multiplex SLE pedigrees. There was strong familial aggregation of antinuclear antibodies (ANAs), anti-double-stranded DNA (dsDNA), anti-La/SSB, anti-Ro/SSA, anti-Sm, anti-nRNP (nuclear ribonucleoprotein), IgM antiphospholipid (aPL) antibodies (Abs) and rheumatoid factor (RF) across these families enriched for lupus. We performed genome-wide linkage analyses in an effort to map genes that contribute to the production of the following autoantibodies: Ro/SSA, La/SSB, nRNP, Sm, dsDNA, RF, nuclear and phospholipids. Using an approach to minimize false positives and adjust for multiple comparisons, evidence for linkage was found to anti-La/SSB Abs on chromosome 3q21 (adjusted P=1.9 x 10(-6)), to anti-nRNP and/or anti-Sm Abs on chromosome 3q27 (adjusted P=3.5 x 10(-6)), to anti-Ro/SSA and/or anti-La/SSB Abs on chromosome 4q34-q35 (adjusted P=3.4 x 10(-4)) and to anti-IgM aPL Abs on chromosome 13q14 (adjusted P=2.3 x 10(-4)). These results support the hypothesis that autoantibody production is a genetically complex trait. Identification of the causative alleles will advance our understanding of critical molecular mechanisms that underlie SLE and perhaps other autoimmune diseases.

Black or African American↗
PubMed2004

Genome scan for QTLs underlying bone size variation at 10 refined skeletal sites: genetic heterogeneity and the significance of phenotype refinement.

To identify quantitative trait loci (QTLs) underlying variation in bone size, we conducted a whole-genome linkage scan in 53 pedigrees with 630 subjects using 380 microsatellite markers. Lumbar area 1, 2, 3, and 4 at the spine, femoral neck, trochanter, intertrochanter areas at the hip, ultradistal, mid-distal, and one-third distal areas at the wrist were measured by dual-energy X-ray absorptiometry (DXA), and adjusted for age, height, weight, and sex. Two-point and multipoint linkage analyses were performed for skeletal bone size at each site and their composite measurements using the SOLAR package. Two chromosomal regions (1q22 and 10q21) were identified with significant evidence of linkage (LOD > 4.32) to one-third distal area, and three were identified with suggestive evidence of linkage (LOD > 2.93) to bone size in one skeletal site. Our results indicated that the low power of QTLs mapping for composite phenotypic measurements may result from genetic heterogeneity of complex traits.

Bone and Bones↗
PubMed1999

Differential response to dietary fat in large (LG/J) and small (SM/J) inbred mouse strains.

The "large" (LG/J) and "small" (SM/J) inbred mouse strains differ for a wide variety of traits related to body size and obesity. Ninety-three LG/J and SM/J mice were divided into two treatment categories and fed a moderately high-fat diet (21% kcal fat) or a low-fat diet (12% kcal fat) from weaning to necropsy. Strain differences in obesity-related traits and differential response to dietary fat increases were analyzed using ANOVA. LG/J animals grow faster from 3 to 10 wk, have longer tails, and have heavier body weight, liver weight, and fat pad weight than SM/J animals. SM/J animals grow faster after 10 wk of age and have higher fasting glucose levels than LG/J animals. SM/J mice were more responsive to increased dietary fat than LG/J mice for growth after 10 wk, necropsy weight, liver weight, fat pad weights, and fasting glucose levels (in males). The growth from 3 to 10 wk had a much greater response in the LG/J strain, whereas tail length had no response. This pattern of dietary response is similar to that expected under the "thrifty" phenotype hypothesis. Genes affecting strain differences and the differential response of the strains to dietary fat can be successfully mapped in the intercross of the LG/J and SM/J strains. This intercross provides an excellent multigenic model for the genetic basis of complex traits and diseases related to body size and obesity.

Adipose Tissue↗
PubMed2006

Association of single nucleotide polymorphisms of the insulin gene with chicken early growth and fat deposition.

Growth rate, body composition, and fat deposition are important traits in chickens. Insulin plays important roles in hepatic cells, muscle cells, and adipose tissue cells. The purpose of the present study was to analyze association of the insulin (INS) gene with chicken growth and body composition traits. Using a F2 design resource population constructed with the crossing of Chinese native Xinghua chickens and White Recessive Rock chickens, the association of 4 single nucleotide polymorphisms (SNP; A+428G, C+1549T, T+3737C, and A+3971G) of INS gene with 13 growth and body composition traits was studied. The T+3737C genotypes were significantly associated with small intestine length (P = 0.0002), and the A+3971G genotypes were significantly associated with early growth (hatch weight and BW at 28 d of age) (P < 0.0001), breast angle (P = 0.0002), and small intestine length (P < 0.0001). None of the 4 SNP was significantly associated with abdominal fat pad weight (P > 0.05). The haplotypes based on the 4 SNP were also significantly associated with early growth (hatch weight and BW at 28 d of age; P < 0.0001) and breast angle (P < 0.0001) but not with small intestine length (P = 0.0505). These results suggested that variation of the insulin gene was significantly associated with chicken early growth but not with fat deposition. In addition, the data from the present study supported the inference that both the one-SNP-at-a-time and the haplotype-based approaches have their own advantages and disadvantages when association analysis of one SNP and haplotypes with chicken complex traits was conducted.

Animals↗
PubMed2002

Identification and ranking of genetic and laboratory environment factors influencing a behavioral trait, thermal nociception, via computational analysis of a large data archive.

Laboratory conditions in biobehavioral experiments are commonly assumed to be 'controlled', having little impact on the outcome. However, recent studies have illustrated that the laboratory environment has a robust effect on behavioral traits. Given that environmental factors can interact with trait-relevant genes, some have questioned the reliability and generalizability of behavior genetic research designed to identify those genes. This problem might be alleviated by the identification of the most relevant environmental factors, but the task is hindered by the large number of factors that typically vary between and within laboratories. We used a computational approach to retrospectively identify and rank sources of variability in nociceptive responses as they occurred in a typical research laboratory over several years. A machine-learning algorithm was applied to an archival data set of 8034 independent observations of baseline thermal nociceptive sensitivity. This analysis revealed that a factor even more important than mouse genotype was the experimenter performing the test, and that nociception can be affected by many additional laboratory factors including season/humidity, cage density, time of day, sex and within-cage order of testing. The results were confirmed by linear modeling in a subset of the data, and in confirmatory experiments, in which we were able to partition the variance of this complex trait among genetic (27%), environmental (42%) and genetic x environmental (18%) sources.

Animals↗
PubMed2003

Adjusting for covariates on a slippery slope: linkage analysis of change over time.

BACKGROUND: We analyzed the Genetic Analysis Workshop 13 (GAW13) simulated data to contrast and compare different methods for the genetic linkage analysis of hypertension and change in blood pressure over time. We also examined methods for incorporating covariates into the linkage analysis. We used methods for quantitative trait loci (QTL) linkage analysis with and without covariates and affected sib-pair (ASP) analysis of hypertension followed by ordered subset analysis (OSA), using variables associated with change in blood pressure over time. RESULTS: Four of the five baseline genes and one of the three slope genes were not detected by any method using conventional criteria. OSA detected baseline gene b35 on chromosome 13 when using the slope in blood pressure to adjust for change over time. Slope gene s10 was detected by the ASP analysis and slope gene s11 was detected by QTL linkage analysis as well as by OSA analysis. Analysis of null chromosomes, i.e., chromosomes without genes, did not reveal significant increases in type I error. However, there were a number of genes indirectly related to blood pressure detected by a variety of methods. CONCLUSIONS: We noted that there is no obvious first choice of analysis software for analyzing a complicated model, such as the one underlying the GAW13 simulated data. Inclusion of covariates and longitudinal data can improve localization of genes for complex traits but it is not always clear how best to do this. It remains a worthwhile task to apply several different approaches since one method is not always the best.

Blood Pressure↗
PubMed2004

Simultaneous mapping of epistatic QTL in chickens reveals clusters of QTL pairs with similar genetic effects on growth.

We used simultaneous mapping of interacting quantitative trait locus (QTL) pairs to study various growth traits in a chicken F2 intercross. The method was shown to increase the number of detected QTLs by 30 % compared with a traditional method detecting QTLs by their marginal genetic effects. Epistasis was shown to be an important contributor to the genetic variance of growth, with the largest impact on early growth (before 6 weeks of age). There is also evidence for a discrete set of interacting loci involved in early growth, supporting the previous findings of different genetic regulation of early and late growth in chicken. The genotype-phenotype relationship was evaluated for all interacting QTL pairs and 17 of the 21 evaluated QTL pairs could be assigned to one of four clusters in which the pairs in a cluster have very similar genetic effects on growth. The genetic effects of the pairs indicate commonly occurring dominance-by-dominance, heterosis and multiplicative interactions. The results from this study clearly illustrate the increase in power obtained by using this novel method for simultaneous detection of epistatic QTL, and also how visualization of genotype-phenotype relationships for epistatic QTL pairs provides new insights to biological mechanisms underlying complex traits.

Algorithms↗
PubMed1997

Construction and characterization of a 10-genome equivalent yeast artificial chromosome library for the laboratory rat, Rattus norvegicus.

Increasing attention has been focused in recent years on the rat as a model organism for genetic studies, in particular for the investigation of complex traits, but progress has been limited by the lack of availability of large-insert genomic libraries. Here, we report the construction and characterization of an arrayed yeast artificial chromosome (YAC) library for the rat genome containing approximately 40,000 clones in the AB1380 host using the pCGS966 vector. An average size of 736 kb was estimated from 166 randomly chosen clones; thus the library provides 10-fold coverage of the genome, with a 99.99% probability of containing a unique sequence. Eight of 39 YACs analyzed by fluorescence in situ hybridization were found to be chimeric, indicating a proportion of about 20-30% of chimeric clones. The library was spotted on high-density filters to allow the identification of YAC clones by hybridization and was pooled using a 3-dimensional scheme for screening by PCR. Among 48 probes used to screen the library, an average of 9.3 positive clones were found, consistent with the calculated 10-fold genomic coverage of the library. This YAC library represents the first large-insert genomic library for the rat. It will be made available to the research community at large as an important new resource for complex genome analysis in this species.

Animals↗
PubMed2006

Genotype-by-sex interaction in the aetiology of type 2 diabetes mellitus: support for sex-specific quantitative trait loci in Hypertension Genetic Epidemiology Network participants.

AIMS/HYPOTHESIS: While there are sex-related differences in both the prevalence of type 2 diabetes mellitus and disease risk factors, there is only limited research on sex-specific influences on type 2 diabetes aetiology within the same study population. Thus, we assessed genotype-by-sex interaction using a liability threshold model in an attempt to localise sex-specific type 2 diabetes quantitative trait loci (QTLs). SUBJECTS, MATERIALS AND METHODS: Hypertensive siblings and their offspring and/or parents in the Hypertension Genetic Epidemiology Network of the Family Blood Pressure Program were recruited from five field centres. The diabetic phenotype was adjusted for race, study centre, age and non-linear age effects. In total, 567 diabetic individuals were identified in 385 families. Variance component linkage analyses in the combined sample and stratified by sex and race were performed (SOLAR program) using race-specific marker allele frequencies derived from a random sample of participants at each centre. RESULTS: We observed a QTL-specific genotype-by-sex interaction (p=0.009) on chromosome 17 at 31 cM, with females displaying a robust adjusted logarithm of odds (LOD) of 3.0 compared with 0.2 in males and 1.3 in the combined sample. Three additional regions demonstrating suggestive evidence for linkage were detected: chromosomes 2 and 5 in the female sample and chromosome 22 (adjusted LOD=1.9) in the combined sample. CONCLUSIONS/INTERPRETATION: These findings suggest that multiple genes may regulate susceptibility to type 2 diabetes, demonstrating the importance of considering the interaction of genes and environment in the aetiology of common complex traits.

Adult↗
PubMed2000

Genetic diversity in the matrix metalloproteinase family. Effects on function and disease progression.

Atherosclerosis is an example of a complex trait, where the course of the disease is influenced by a combination of common variation in a constellation of genes and the effect of a wide range of environmental variables. Thus, the underlying disease mechanisms will be modulated by genetic diversity and the effect this diversity has on an individual's response to environmental challenges such as smoking, diet, and exercise. Unlike the consequences of mutations in severe single-gene disorders on protein function, the impact of individual common, functionally important sequence changes in genes contributing to multifactorial diseases is likely to be very small. The challenge is to dissect the contribution that each of these genes makes to the disease process. We have tackled this by identifying common genetic variants, studying their effects on function, and applying them to the analysis of association in appropriately structured and suitably powered studies. Even with our incomplete understanding of the disease, the list of potential candidate genes we could study is vast; but, we do know from pathological studies that a wide spectrum of structural architecture exists in atherosclerotic plaques, suggesting that remodeling of vascular connective tissue is fundamentally important. Matrix remodeling is controlled by a complex network of cell and matrix interactions, the net outcome of which is the product of a balance between synthetic and degradative processes. Our work has focused on the family of enzymes and inhibitors most directly associated with matrix turnover--the matrix metalloproteinases (MMPs) and their natural inhibitors (TIMPs, tissue inhibitors of MPs). We specifically searched for functionally relevant genetic variants that might modulate the delicate control of matrix turnover. Using these molecular genetic strategies to investigate the impact of natural genetic variation on vascular matrix remodeling has begun to shed new light on the importance of these genes in atherogenesis.

Arteriosclerosis↗
PubMed2002

Regression models for allele sharing: analysis of accumulating data in affected sib pair studies.

Advances in human genome mapping have led to the identification of large numbers of genetic markers that allow systematic searches for multiple disease susceptibility genes for complex traits. A common design involves the recruitment of families with at least two children affected with the disease of interest. The objective is to find chromosomal regions that harbour susceptibility genes for the disease. The affected children, their parents if available, and sometimes other, unaffected, siblings are genotyped using sets of microsatellite DNA markers representing chromosomal sites distributed across the genome. Each marker can occur in several different variants known as alleles, and a pair of alleles constitutes the marker genotype. Each child randomly inherits one of their mother's two alleles and one of their father's two alleles. If a marker is close to a disease susceptibility gene, then affected siblings are expected to have more sharing of the same maternal and/or paternal marker alleles. Statistical methods are used to estimate the distribution of allele sharing in each affected sib pair (ASP) using the set of markers typed across each chromosome, and to test for the presence of excess sharing in the families as a group at each point across the genome. Regression models that allow the allele sharing proportions to depend on characteristics of the family such as diagnostic subtype or ethnic background have been developed to address the heterogeneity that is characteristic of complex disease, but these have not yet been widely applied. In this paper, we apply regression modelling to investigate variation associated with family-level covariates and with the order in which families are recruited and genotyped. We also discuss how some of the concepts of group sequential analysis apply to accumulating data from genome scans of complex disease.

Adolescent↗
PubMed2004

Candidate defense genes as predictors of quantitative blast resistance in rice.

Although quantitative trait loci (QTL) underpin many desirable agronomic traits, their incorporation into crop plants through marker-assisted selection is limited by the low predictive value of markers on phenotypic performance. Here we used candidate defense response (DR) genes to dissect quantitative resistance in rice using recombinant inbred (RI) and advanced backcross (BC) populations derived from a blast-resistant cultivar, Sanhuangzhan 2 (SHZ-2). Based on DNA profiles of DR genes, RI lines were clustered into two groups corresponding to level of resistance. Five DR genes, encoding putative oxalate oxidase, dehydrin, PR-1, chitinase, and 14-3-3 protein, accounted for 30.0, 23.0, 15.8, 6.7, and 5.5% of diseased leaf area (DLA) variation, respectively. Together, they accounted for 60.3% of the DLA variation and co-localized with resistance QTL identified by interval mapping. Average phenotypic contributions of oxalate oxidase, dehydrin, PR-1, chitinase, and 14-3-3 protein in BC lines were 26.1, 19.0, 18.0, 11.5, and 10.6%, respectively, across environments. Advanced BC lines with four to five effective DR genes showed enhanced resistance under high disease pressure in field tests. Our results demonstrate that the use of natural variation in a few candidate genes can solve a long-standing problem in rice production and has the potential to address other problems involving complex traits.

DNA, Plant↗
PubMed1999

Nitrogen-induced changes in morphological development and bacterial susceptibility of belgian endive (Cichorium intybus L.) are genotype-dependent

Nitrogen is known to modulate plant development and resistance to pathogens. Four selected lines (Alg, NS1, NR1 and NR2) of chicory (Cichorium intybus L.) were grown on low (0.6 mM) and high (3 mM) NO(-)(3) nutrition in order to study the effect of N on the expression of three traits, namely, shoot/root ratio, chicon morphology and resistance to soft rot caused by Erwinia sp. For all genotypes, increasing N supply led to a higher shoot/root ratio, resulting from an increased shoot biomass but with no effect on root growth. In contrast, the effect of N on chicon morphology and resistance to bacteria was genotype-dependent and we distinguished two groups of lines according to their phenotypic characteristics. In the group consisting of NR1 and NR2, increasing NO(-)(3) supply during the vegetative phase made the chicon morphology switch from an opened to a closed type while resistance to bacteria was not affected by N supply. In the NS1 and Alg group, the effect of N on chicon morphology was the opposite to that observed in the NR1-NR2 group while NS1 and Alg exhibited a partial resistance to Erwinia sp. , only expressing soft-rot disease when the N supply reached 3 mM. Characterization by DNA amplification fingerprinting (DAF) allowed the generation of 110 polymorphic bands and confirmed that the lines NR1 and NR2, on the one hand, and NS1 and Alg, on the other hand, belong to two distinct genetic groups. The DAF results indicate that chicon morphology and partial resistance to Erwinia sp. are complex traits which would be amenable to quantitative trait loci analysis. The split growth phase of chicory means that any changes in chicon related to N supply during vegetative growth were mediated by a root-originating signal. No variation in root carbon content among genotypes and NO(-)(3) treatments was observed. In contrast, differences in root N content revealed the same grouping of the chicory lines, NR1 and NR2 being systematically richer in amino acids and NO(-)(3) than NS1 and Alg. However, no correlation existed between N compounds and chicon morphology or pathology if all genotypes were considered together. Thus, the effect of N on plant development and pathology as well as putative identified signals might be specific for a genotype. Our study indicates that it is necessary to consider the genetic variability within a species in any signalling-pathway research.

Journal Article↗
PubMed2004

A centromeric region on chromosome 6(6H) affects dormancy in an induced mutant in barley.

Genetic control of seed dormancy in barley (Hordeum vulgare L.) has mostly been described in terms of quantitative variation. Although some molecular markers for dormancy QTL have been identified, the corresponding genes involved in the regulation of the process have not been cloned. Induced barley mutants may constitute useful material to study the physiology and genetics of seed dormancy. The objective of this study was to identify the genetic control of this trait in a mutant (TL43) produced in the barley cv. Triumph. This mutant was selected for reduced dormancy and reduced sensitivity to abscisic acid (ABA). Two sets of F6 barley lines were selected for high and low levels of dormancy from a cross between the original dormant parent and the sodium azide-induced non-dormant TL43 mutant. Unexpectedly, given the near-isogenic nature of these two genotypes, polymorphism was detected for an SSR located in the centromeric region of chromosome 6(6H) out of a total of 92 molecular markers evenly distributed along the genome. Fortunately, upon three cycles of intensive divergent selection, every dormant and non-dormant F5 line consistently showed the genotype for this region identical to Triumph and TL43, respectively. Based on the mutagenic effect presumably attributed to sodium azide, mostly single point mutations, it cannot be clearly established if such extensive genomic variation on chromosome 6(6H) is due to the mutagenic treatment or may be an introgression from an unknown source. The means that could originate such heterogeneity are discussed; however, regardless of its origin, this genomic region shows a strong association with the expression of seed dormancy and provides an additional genetic locus for further studies of the mechanistic basis of this complex trait. In addition, since TL43 shows reduced sensitivity to ABA, the response to this hormone was determined on the F6 seed from the two sets of selected F5 lines. The results confirmed that the initial level of dormancy in the seed lot is the most important factor in determining ABA sensitivity.

Abscisic Acid↗
PubMed2002

Characterization of mutants with reduced seed dormancy at two novel rdo loci and a further characterization of rdo1 and rdo2 in Arabidopsis.

Seed dormancy and germination are complex traits that are controlled by many genes. Four mutants in Arabidopsis thaliana exhibiting a reduced dormancy phenotype, designated rdo1, rdo2, rdo3, and rdo4, have been characterized, both genetically and physiologically. Two of these mutants, rdo1 and rdo2, have been described before, the other two represent novel loci. The mutants mapped on chromosome 1 (rdo3), chromosome 2 (rdo2 and rdo4), and chromosome 3 (rdo1). None of these loci has been related to dormancy before. All four mutants show pleiotropic effects in the adult plant stage, which are different for each mutant. None of the mutants is deficient in ABA. Compared to Ler (wild-type), ABA sensitivity is not altered either, thereby excluding the possibility that ABA is involved in causing the reduced dormancy phenotype. The GA requirement was studied by using the GA biosynthesis inhibitor paclobutrazol, and genetically by generating double mutants with the GA-deficient mutant ga1-3. The results obtained by these two methods were comparable for all but one mutant: rdo1. In a GA-deficient background, rdo1, rdo2 and rdo3, all show sensitivity to GA between that of ga1-3 and ga1-3 aba1. However, when using paclobutrazol rdo1 exhibited the same sensitivity as rdo4 and wild-type. Analysis of double mutants among the rdo mutants revealed a very complex and inconsistent pattern.

Journal Article↗
PubMed2026

The genomic origins and evolutionary path to a key innovation in the world's most venomous snakes.

Evolutionary innovation is a catalyst for the colonization of new environments and the adaptive radiations of major groups. Novel traits typically evolve through the modification of preexisting characters, but the genetic paths underlying their origin have been challenging to trace, and the general requirements for and relative order of different kinds of gene mutations have been difficult to assess. Here, we trace the genomic origins of four procoagulant venom toxins (factor X, factor V, group I phospholipase A2, and Kunitz-type toxins) that collectively underlie a novel, especially potent blood-clotting venom type in the recently evolved Australian brown snake and taipan clade. We find evidence for a previously unknown fifth toxin, coagulation factor VII, and show that the toxins evolved through two distinct genetic paths. The factor X and factor V toxins evolved through the sequential de novo co-option of ancestral clotting factor proteins that entailed their heterotopic expression in the venom gland, the fixation of segmental duplications containing each locus, and subsequent gain-of-function mutations that rendered factor X and factor V constitutively active. In contrast, the phospholipase A2 and Kunitz-type toxins evolved by modifying the functions of neurotoxins that were part of the venom arsenal. Our findings support models in which innovative mutations in single-copy genes precede gene duplication in the evolution of novel proteins and offer a rare view into the genesis of a complex trait that has played a central role in a major adaptive radiation.

Animals↗
PubMed2026

The genomic origins and evolutionary path to a key innovation in the world's most venomous snakes.

Evolutionary innovation is a key driver of the colonization of new environments and the adaptive radiations of major groups. Novel traits typically evolve through the modification of pre-existing characters but the genetic paths underlying their origin have been challenging to trace, and the general requirements for and relative order of different kinds of gene mutations have been difficult to assess. Here, we trace the genomic origins of four procoagulant venom toxins (factor X, factor V, group I phospholipase A2, and Kunitz-type toxins) that collectively underlie a novel, especially potent blood-clotting venom type in the recently evolved Australian brown snake and taipan clade. We discover evidence for a previously unknown fifth toxin, coagulation factor VII, and show that the toxins evolved through two distinct genetic paths. The factor X and factor V toxins evolved through the sequential de novo co-option of ancestral clotting factor proteins that entailed their heterotopic expression in the venom gland, the fixation of segmental duplications containing each locus, and subsequent gain-of-function mutations that rendered factor X and factor V constitutively active. In contrast, the phospholipase A2 and Kunitz-type toxins evolved by modifying the functions of neurotoxins that were part of the venom arsenal. Our findings support models in which innovative mutations in single-copy genes precede gene duplication in the evolution of novel proteins and offer a rare view into the genesis of a complex trait that has played a central role in a major adaptive radiation.

Biological Sciences: Evolution↗