Preservation of duplicate genes by originalization

Neofunctionalization, subfunctionalization and increasing gene dosage were proposed to be the possible ways to explain duplicate-gene preservation in previous studies. However, in some natural populations, such as yeast Saccharomyces cerevisiae, a considerable proportion of the duplicate genes originated from ancient whole genomic duplication (WGD) is preserved till now, which cannot be sufficiently explained by these mechanisms. In this article, we present another possible way to explain this conundrum—originalization, by which duplicate genes are both preserved intact at a high frequency in the population under only purifying selection. With approximate equal rates of mutation at the two duplicated loci, analytical, numerical and simulation results consistently show that the mean time to nonfunctionalization for unlinked haploinsufficient gene duplication might become markedly prolonged, which results from originalization. These theoretical results imply that originalization might be an alternative effective and temporary way of preserving duplicate genes.     

Genome Changes After Gene Duplication: Haploidy vs. Diploidy

Since genome size and the number of duplicate genes observed in genomes increase from haploid to diploid organisms, diploidy might provide more evolutionary probabilities through gene duplication. It is still unclear how diploidy promotes genomic evolution in detail. In this study, we explored the evolution of segmental gene duplication in haploid and diploid populations by analytical and simulation approaches. Results show that (1) under the double null recessive (DNR) selective model, given the same recombination rate, the evolutionary trajectories and consequences are very similar between the same-size gene-pool haploid vs. diploid populations; (2) recombination enlarges the probability of preservation of duplicate genes in either haploid or diploid large populations, and haplo-insufficiency reinforces this effect; and (3) the loss of duplicate genes at the ancestor locus is limited under recombination while under complete linkage the loss of duplicate genes is always random at the ancestor and newly duplicated loci. Therefore, we propose a model to explain the advantage of diploidy: diploidy might facilitate the increase of recombination rate, especially under sexual reproduction; more duplicate genes are preserved under more recombination by originalization (by which duplicate genes are preserved intact at a special quasi-mutation-selection balance under the DNR or haplo-insufficient selective model), so genome sizes and the number of duplicate genes in diploid organisms become larger. Additionally, it is suggested that small genomic rearrangements due to the random loss of duplicate genes might be limited under recombination.USUALLY genome size becomes larger from haploid to diploid organisms (Lynch and Conery 2003), and so does the number of duplicate genes observed in genomes (Zhang 2003). It is extensively hypothesized that diploidy might facilitate the preservation and accumulation of duplicate genes, but it is still unclear how diploidy supports the evolution of duplicate genes in detail. The superiority of diploidy is classically attributed to preventing expression of deleterious mutations (Crow and Kimura 1965), but it is also argued that the sheltering of deleterious mutations cannot adequately explain the advantages of diploidy (Perrot et al. 1991).Recombination is a common phenomenon in all three kingdoms of life, Bacteria, Eukarya, and Archaea. It has been reported that recombination influences the loss of duplicate genes (Zhang and Kishino 2004; Xue et al. 2010). In diploid organisms, if recombination between the ancestor locus and the newly duplicated locus is free, the rate of recombination is maximally 0.5, which is commonly observed especially when the two loci are located on different chromosomes. Although recombination should not be regarded as an exception in haploid organisms (Fraser et al. 2007), recombination events usually occur more frequently in diploid populations than they do in haploid populations. In other words, diploidy might facilitate the occurrence of recombination. The difference of recombination behaviors between haploid and diploid organisms is an obvious and important feature during genomic evolution.In our recent studies of genomic duplication, we proposed a new possible way of preserving and accumulating duplicate genes in genomes—originalization (Xue and Fu 2009a). As is well known, for a locus in an infinite diploid population, the frequencies of wild-type and degenerative alleles will move to an equilibrium under purifying selection and mutation, which is known as the mutation–selection balance. After genomic duplication, under two simple selective models, double null recessive (DNR, under which valid individuals require at least one active wild-type allele on the ancestor and newly duplicated loci) and haplo-insufficient (HI or partial dominant, under which valid individuals require at least two active wild-type alleles on both loci) models, a special equilibrium of allele frequencies at the ancestor and newly duplicated loci will be reached under recombination, in which the frequency of wild-type allele is kept high at both loci. Under the HI selective model this balance becomes so stable and flexible that the fixation of a degenerative allele at one of these two loci (or the balance being broken) becomes very difficult even in a modest population (Xue and Fu 2009a,b). However, if the two loci are tightly linked (recombination rate r = 0), this balance of allele frequencies does not appear. As r increases, the balance becomes more stable and the frequency of the wild-type allele at two loci becomes higher. High frequency of the wild-type allele at both loci means that duplicate genes are preserved intact in genomes, so this phenomenon was named originalization.Although many duplicate genes originated from genomic duplications in some species, such as yeast, maize, and fish (Li et al. 2005), those from segmental duplications are also very popular (Zhang et al. 2000; Leister 2004). In haploid populations, most duplication events are small segmental duplications. Therefore, to understand genomic evolution comprehensively, it is necessary to explore the evolution of segmental genomic duplication.Lynch et al. (2001) and Tanaka et al. (2009) have studied the evolution of segmental gene duplication in diploid populations theoretically. However, in this study, we further compared the evolution of segmental gene duplication in haploid vs. diploid populations by numerical and simulation approaches under the DNR and HI selective models. We observed that haploid and diploid populations with the same-size gene pool are very similar under the DNR model and the same recombination rate. Recombination enlarges the probability of preservation of duplicate genes in either haploid or diploid populations via originalization, and haplo-insufficiency reinforces this effect. The loss of duplicate genes at the ancestor locus might be limited under recombination, while under complete linkage, the loss of duplicate genes is random at the ancestor and newly duplicated loci. According to these results, we propose a model with which to explain the revolutionary genomic transition from haploidy to diploidy.     

p53 polymorphisms in Russia and Belarus: correlation of the 2-1-1 haplotype frequency with longitude

Four different polymorphisms in the human p53 gene (a 16-bp duplication in intron 3, and three RFLPs: for Bsh1236I at codon 72, for MspI in intron 6 and for BamHI in the 3 flanking region) and extended haplotypes were studied in nine geographically diverse populations from Russia and Belarus. The Yakuts differed from all other populations, as they had a significantly higher frequency of the BamHI A1 allele. Most populations did not differ significantly from each other in the frequency of the Bsh1236I polymorphism. The 16-bp duplication A1 allele and MspI A2 allele frequencies were significantly higher in the Yakut and Khant populations. Linkage disequilibrium values (D) between BamHI and other polymorphic sites were not significant in many cases; for this reason we have used the 16 bp–Bsh1236I–MspI haplotype frequencies only. Of eight possible haplotypes, five were observed in the populations investigated. Haplotype 1-2-2 was the most frequent in all populations. The next most common haplotype, 1-1-2, was present at very similar frequencies among the Byelorussians and Russians from Smolensk, but was more frequent in other populations. The frequency of haplotype 2-1-1 showed a nearly continuous decrease from West to East (from 17.857% among the Byelorussians to 0.685% in the Yakuts from the Verkhoyansk) and correlated with longitude (Spearmans r=–0.8667, P=0.0025), which may be due to natural selection and adaptation. The relationships among populations were evaluated by means of Neis D_A distances for the 16 bp–Bsh1236I–MspI haplotype frequencies. Based on the multidimensional scaling analysis a correlation between p53 haplotype frequencies and ethnicity is supposed.     

High Frequency Repeat-Induced Point Mutation (Rip) Is Not Associated with Efficient Recombination in Neurospora

Duplicated DNA sequences in Neurospora crassa are efficiently detected and mutated during the sexual cycle by a process named repeat-induced point mutation (RIP). Linked, direct duplications have previously been shown to undergo both RIP and deletion at high frequency during premeiosis, suggesting a relationship between RIP and homologous recombination. We have investigated the relationship between RIP and recombination for an unlinked duplication and for both inverted and direct, linked duplications. RIP occurred at high frequency (42-100%) with all three types of duplications used in this study, yet recombination was infrequent. For both inverted and direct, linked duplications, recombination was observed, but at frequencies one to two orders of magnitude lower than RIP. For the unlinked duplication, no recombinants were seen in 900 progeny, indicating, at most, a recombination frequency nearly three orders of magnitude lower than the frequency of RIP. In a direct duplication, RIP and recombination were correlated, suggesting that these two processes are mechanistically associated or that one process provokes the other. Mutations due to RIP have previously been shown to occur outside the boundary of a linked, direct duplication, indicating that RIP might be able to inactivate genes located in single-copy sequences adjacent to a duplicated sequence. In this study, a single-copy gene located between elements of linked duplications was inactivated at moderate frequencies (12-14%). Sequence analysis demonstrated that RIP mutations had spread into these single-copy sequences at least 930 base pairs from the boundary of the duplication, and Southern analysis indicated that mutations had occurred at least 4 kilobases from the duplication boundary.     

Population structure in admixed populations: effect of admixture dynamics on the pattern of linkage disequilibrium

Gene flow between genetically distinct populations creates linkage disequilibrium (admixture linkage disequilibrium [ALD]) among all loci (linked and unlinked) that have different allele frequencies in the founding populations. We have explored the distribution of ALD by using computer simulation of two extreme models of admixture: the hybrid-isolation (HI) model, in which admixture occurs in a single generation, and the continuous-gene-flow (CGF) model, in which admixture occurs at a steady rate in every generation. Linkage disequilibrium patterns in African American population samples from Jackson, MS, and from coastal South Carolina resemble patterns observed in the simulated CGF populations, in two respects. First, significant association between two loci (FY and AT3) separated by 22 cM was detected in both samples. The retention of ALD over relatively large (>10 cM) chromosomal segments is characteristic of a CGF pattern of admixture but not of an HI pattern. Second, significant associations were also detected between many pairs of unlinked loci, as observed in the CGF simulation results but not in the simulated HI populations. Such a high rate of association between unlinked markers in these populations could result in false-positive linkage signals in an admixture-mapping study. However, we demonstrate that by conditioning on parental admixture, we can distinguish between true linkage and association resulting from shared ancestry. Therefore, populations with a CGF history of admixture not only are appropriate for admixture mapping but also have greater power for detection of linkage disequilibrium over large chromosomal regions than do populations that have experienced a pattern of admixture more similar to the HI model, if methods are employed that detect and adjust for disequilibrium caused by continuous admixture.     

Integration of vector-containing Bacillus subtilis chromosomal DNA by a Campbell-like mechanism

Summary Using plasmid pHV60, which contains a chloramphenicol resistance (Cm^r) gene that is expressed in Bacillus subtilis, a set of transformation-deficient strains of B. subtilis was isolated by insertional mutagenesis. When chromosomal DNA from these mutants was used to transform a transformation-proficient B. subtilis strain, almost all of the Cm^r transformants had the mutant phenotype as expected. However, with a frequency of approximately 3×10^-4 atypical transformants with the wild-type phenotype were produced. Data concerning amplification of the DNA containing the Cm^r marker and duplication of DNA sequences are presented that suggest that these atypical transformants are the result of a Campbell-like integration of the chromosomal DNA containing the integrated plasmid. Transductional mapping showed that in the atypical transformants the vector-containing DNA had a strong tendency to integrate at sites adjacent to the original site of integration, although integration at sites elsewhere on the chromosome was also observed. The production of atypical transformants is explained on the basis of integration of chromosomal DNA by a Campbell-like mechanism. Circularization of vector-containing chromosomal DNA is thought to occur through joining of the extremities of single-stranded DNA molecules by fortuitous base pairing with an independently entered single-stranded DNA molecule.     

Study of RecA-independent homologous recombination and a chromosomal rearrangement in the Escherichia coli strain carrying an extended tandem duplication

A heterozygous tandem duplication in the Escherichia coli deo operon region deoA deoB::Tn5/deoC deoD thr::Tn9 with the total length approximately 150 kb, which was obtained in the conjugational mating in the HfrH strain, was examined. By means of digestion with the NotI enzyme, pulsed-field gel electrophoresis, and the conjugational transfer of the duplication in the F- strain, the chromosomal rearrangement, which occurred in the duplication region upon its stabilization in the bacterial genome, was studied. In a more stable strain, two new NotI sites were shown to appear in the chromosomal region located close to the duplication, which might have resulted from the transposition of the IS50 sequence from Tn5. The data were also obtained indicating the possibility of secondary transposition of the chromosomal segment between the two new NotI sites (approximately 30 kb) in the region located near the duplication. With the use of rec+ and recA strains, two types of haploid and diploid segregants generated by the duplication were studied: DeoD+ (the DeoD+ allele is not expressed in the original duplication due to the polar effect of the deoB::Tn5 insertion) and DeoC DeoD. The segregation of DeoD+ clones was shown to be RecA-dependent, whereas the DeoC DeoD segregants selected on the medium that contained thymine at a low concentration (i.e., under conditions of thymine starvation) appeared at a rather high frequency. However, the relative frequency of haploid clones, which have lost the duplication, strongly decreased in the recA genome among segregants of both types.     

Selfish chromosomal drive shapes recent centromeric histone evolution in monkeyflowers

Centromeres are essential mediators of chromosomal segregation, but both centromeric DNA sequences and associated kinetochore proteins are paradoxically diverse across species. The selfish centromere model explains rapid evolution by both components via an arms-race scenario: centromeric DNA variants drive by distorting chromosomal transmission in female meiosis and attendant fitness costs select on interacting proteins to restore Mendelian inheritance. Although it is clear than centromeres can drive and that drive often carries costs, female meiotic drive has not been directly linked to selection on kinetochore proteins in any natural system. Here, we test the selfish model of centromere evolution in a yellow monkeyflower (Mimulus guttatus) population polymorphic for a costly driving centromere (D). We show that the D haplotype is structurally and genetically distinct and swept to a high stable frequency within the past 1500 years. We use quantitative genetic mapping to demonstrate that context-dependence in the strength of drive (from near-100% D transmission in interspecific hybrids to near-Mendelian in within-population crosses) primarily reflects variable vulnerability of the non-driving competitor chromosomes, but also map an unlinked modifier of drive coincident with kinetochore protein Centromere-specific Histone 3 A (CenH3A). Finally, CenH3A exhibits a recent (<1000 years) selective sweep in our focal population, implicating local interactions with D in ongoing adaptive evolution of this kinetochore protein. Together, our results demonstrate an active co-evolutionary arms race between DNA and protein components of the meiotic machinery in Mimulus, with important consequences for individual fitness and molecular divergence.     

Z-Spectrum Analysis Provides Proton Environment Data (ZAPPED): A New Two-Pool Technique for Human Gray and White Matter

A new technique – Z-spectrum Analysis Provides Proton Environment Data (ZAPPED) – was used to map cross-relaxing free and restricted protons in nine healthy subjects plus two brain tumor patients at 3T. First, MT data were acquired over a wide symmetric range of frequency offsets, and then a trio of quantitative biomarkers, i.e., the apparent spin-spin relaxation times (T_2,f, T_2,r) in both free and restricted proton pools as well as the restricted pool fraction F_r, were mapped by fitting the measured Z-spectra to a simple two-Lorentzian compartment model on a voxel-by-voxel basis. The mean restricted exchangeable proton fraction, F_r, was found to be 0.17 in gray matter (GM) and 0.28 in white matter (WM) in healthy subjects. Corresponding mean values for apparent spin-spin relaxation times were 785 µs (T_2,f) and 17.7 µs (T_2,r) in GM, 672 µs (T_2,f) and 23.4 µs (T_2,r) in WM. The percentages of F_f and F_r in GM are similar for all ages, whereas F_r shows a tendency to decrease with age in WM among healthy subjects. The patient ZAPPED images show higher contrast between tumor and normal tissues than traditional T₂-weighted and T₁-weighted images. The ZAPPED method provides a simple phenomenological approach to estimating fractions and apparent T₂ values of free and restricted MT-active protons, and it may offer clinical useful information.     

Time to fixation in the presence of recombination

We study the evolutionary dynamics of a haploid population of infinite size recombining with a probability r in a two locus model. Starting from a low fitness locus, the population is evolved under mutation, selection and recombination until a finite fraction of the population reaches the fittest locus. An analytical method is developed to calculate the fixation time T to the fittest locus for various choices of epistasis. We find that: (1) for negative epistasis, T decreases slowly for small r but decays fast at larger r; (2) for positive epistasis, T increases linearly for small r and mildly for large r; (3) for compensatory mutation, T diverges as a power law with logarithmic corrections as the recombination fraction approaches a critical value. Our calculations are seen to be in good agreement with the exact numerical results.     

On the genealogy of a duplicated microsatellite

When a microsatellite locus is duplicated in a diploid organism, a single pair of PCR primers may amplify as many as four distinct alleles. To study the evolution of a duplicated microsatellite, we consider a coalescent model with symmetric stepwise mutation. Conditional on the time of duplication and a mutation rate, both in a model of completely unlinked loci and in a model of completely linked loci, we compute the probabilities for a sampled diploid individual to amplify one, two, three, or four distinct alleles with one pair of microsatellite PCR primers. These probabilities are then studied to examine the nature of their dependence on the duplication time and the mutation rate. The mutation rate is observed to have a stronger effect than the duplication time on the four probabilities, and the unlinked and linked cases are seen to behave similarly. Our results can be useful for helping to interpret genetic variation at microsatellite loci in species with a very recent history of gene and genome duplication.     

Populational interactions among underdominant chromosome rearrangements help them to persist in small demes

Populational interactions among unlinked chromosomal rearrangements with partial heterozygote sterility and multiplicative fitness were studied to verify whether they help such rearrangements to persist in small populations, in spite of a considerable migration rate with a large population. A deterministic island-continent model was studied by exact recurrence relations connecting gametic frequencies in successive generations. The increase in the number of chromosomal rearrangements with the same sterility rate (s) causes an increase in the critical value of the migration rate (m_c) over which the chromosomal rearrangements are eliminated from the small population, mainly for medium s values (0.2 ≤ s ≤ 0.5) (“reciprocal stabilization” of the chromosomal rearrangements). A comparison was made between the velocities of the fixation of a few rearrangements with high heterozygote sterility (low n/high s) and that of many rearrangements with low heterozygote sterility (high n/low s), to reach a given level of populational stability of the rearranged karyotype measured by m_c. The former process was shown to be more rapid in small demes, the latter in large ones. However, the increase in the number of unlinked chromosomal rearrangements is more efficient in reducing the neutral gene flow than in increasing the populational stability of the rearranged karyotype.     

Evolutionary Patterns of Gene Families Generated in the Early Stage of Vertebrates

In this paper we have analyzed 49 vertebrate gene families that were generated in the early stage of vertebrates and/or shortly before the origin of vertebrates, each of which consists of three or four member genes. We have dated the first (T₁) and second (T₂) gene duplications of 26 gene families with 3 member genes. The means of T₁ (594 mya) and T₂ (488 mya) are largely consistent to a well-cited version of two-round (2R) genome duplication theory. Moreover, in most cases, the time interval between two successive gene duplications is large enough that the fate of duplicate genes generated by the first gene duplication was likely to be determined before the second one took place. However, the phylogenetic pattern of 23 gene families with 4 members is complicated; only 5 of them are predicted by 2R model, but 11 families require an additional gene (or genome) duplication. For the rest (7 families), at least one gene duplication event had occurred before the divergence between vertebrate and Drosophila, indicating a possible misleading of the 4:1 rule (member gene ratio between vertebrates and invertebrates). Our results show that Ohno's 2R conjecture is valid as a working hypothesis for providing a most parsimonious explanation. Although for some gene families, additional gene duplication is needed, the credibility of the third genome duplication (3R) remains to be investigated. Received: 13 December 1999 / Accepted: 7 April 2000     

The Impact of Iodine Excess on Thyroid Hormone Biosynthesis and Metabolism in Rats

Thyroid function ultimately depends on appropriate iodine supply to the gland. There is a complex series of checks and balances that the thyroid uses to control the orderly utilization of iodine for hormone synthesis. The aim of our study is to evaluate the mechanism underlying the effect of iodine excess on thyroid hormone metabolism. Based on the successful establishment of animal models of normal-iodine (NI) and different degrees of high-iodine (HI) intake in Wistar rats, the content of monoiodotyrosine (MIT), diiodotyrosine (DIT), T₄, and T₃ in thyroid tissues, the activity of thyroidal type 1 deiodinase (D1) and its (Dio1) mRNA expression level were measured. Results showed that, in the case of iodine excess, the biosynthesis of both MIT and DIT, especially DIT, was increased. There was an obvious tendency of decreasing in MIT/DIT ratio with increased doses of iodine intake. In addition, iodine excess greatly inhibited thyroidal D1 activity and mRNA expression. T₃ was greatly lower in the HI group, while there was no significant difference of T₄ compared with NI group. The T₃/T₄ ratio was decreased in HI groups, antiparalleled with increased doses of iodine intakes. In conclusion, the increased biosyntheses of DIT relative to MIT and the inhibition of thyroidal Dio1 mRNA expression and D1 activity may be taken as an effective way to protect an organism from impairment caused by too much T₃. These observations provide new insights into the cellular regulation mechanism of thyroid hormones under physiological and pathological conditions.     

Mendel's First Law: partisan interests and the parliament of genes

Mendel’s First Law requires explanation because of the possibility of ‘meiotic drivers’, genes that distort fair segregation for selfish gain. The suppression of drive, and the restoration of fair segregation, is often attributed to genes at loci unlinked to the drive locus—such genes cannot benefit from drive but do suffer its associated fitness costs. However, selection can also favour suppressors at loci linked to the drive locus, raising the question of whether suppression of drive usually comes from linked or unlinked loci. Here, I study linked and unlinked suppression in a two-locus model with initial stable polymorphism at the drive locus. I find that the invasion rate of suppressors is a decreasing function of the recombination fraction between the drive and suppressor loci. Surprisingly, the relative likelihood of unlinked vs. linked suppression increases with the strength of drive and is insensitive to the fitness costs of the driver allele. I find that the chromosomal position of the driver influences how rapidly it is suppressed, with a driver in the middle of a chromosome suppressed more rapidly than a driver near the tip. When drive is strong, only a small number of chromosomes are required for suppression usually to derive from unlinked loci. In contrast, when drive is weak, and especially when suppressor alleles are associated with fitness costs, suppression will usually come from linked loci unless the genome comprises many chromosomes.Subject terms: Evolutionary genetics, Population genetics     

Molecular mechanisms of self-incompatibility in Brassica

In Brassica species, self-incompatibility has been mapped genetically to a single chromosomal location. In this region several closely linked genes have been identified. One of them, S-locus receptor kinase (SRK), determines S haplotype specificity of the stigma and it's the key protein for SI reaction. The role of the S locus glycoprotein (SLG) gene remains unclear. In the last decade approximately 15 additional genes linked to S-locus have been found. Recently, a gene has been identified (SCR) that encodes a small cysteine-rich protein which is a candidate for the pollen ligand. In addition to S locus linked genes there are unlinked SLRgenes (S-locus related genes). In this review, we discuss the role of these genes and the current view on the self-incompatibility mechanism in Brassica.     

A morphophysiological analysis of the effects of drought and shade on <Emphasis Type="Italic">Catalpa bungei</Emphasis> plantlets

The interactive effects of shade and drought on the morphological and physiological traits of Catalpa bungei plantlets were assessed. Seedling growth, biomass, biomass allocation, leaf morphology, chlorophyll (Chl) content and gas-exchange parameters were measured in plants raised for 3 months under three light levels [80% (HI), 50% (MI), 30% (LI)] and two water levels [moisture (M) and drought (D)]. The results showed that shade greatly decreased growth, biomass, leaf area (LA) and Chl a/b; increased specific leaf area (SLA) and Chl content; and reduced photosynthetic rate (P _n). Drought reduced the growth, biomass, LA, SLA, Chl a/b, P _n, stomatal conductance (G _s), transpiration rate (T _r) and intercellular carbon dioxide concentration (C _i) and increased the Chl content. Stomatal closure was an early physiological response to water stress. Light, water and their interaction significantly affected plant traits and their bivariate relationships. The phenotypic plasticity index of light (0.47) was much higher than that of water (0.21), indicating that light was the main driver of the variations observed. Under drought stress, growth, biomass, leaf and stem biomass allocation significantly decreased in the HI and MI environments, whereas no significant difference was observed in growth or biomass parameters under the LI condition. Furthermore, no significant difference was observed in P _n, G _s, or T _r under the LI condition under water stress. Our results showed that shade did not alter the negative effects caused by drought stress in MI but did alleviate the negative effects of the LI condition. In summary, the effect of drought on C. bungei plantlets depends on the irradiance conditions.     

Implications of Cardiovascular Disease Risk Assessment Using the WHO/ISH Risk Prediction Charts in Rural India

Cardiovascular disease (CVD) risk in India is currently assessed using the World Health Organization/International Society for Hypertension (WHO/ISH) risk prediction charts since no population-specific models exist. The WHO/ISH risk prediction charts have two versions—one with total cholesterol as a predictor (the high information (HI) model) and the other without (the low information (LI) model). However, information on the WHO/ISH risk prediction charts including guidance on which version to use and when, as well as relative performance of the LI and HI models, is limited. This article aims to, firstly, quantify the relative performance of the LI and HI WHO/ISH risk prediction (for WHO-South East Asian Region D) using data from rural India. Secondly, we propose a pre-screening (simplified) point-of-care (POC) test to identify patients who are likely to benefit from a total cholesterol (TC) test, and subsequently when the LI model is preferential to HI model. Analysis was performed using cross-sectional data from rural Andhra Pradesh collected in 2005 with recorded blood cholesterol measurements (N = 1066). CVD risk was computed using both LI and HI models, and high risk individuals who needed treatment(T _HR) were subsequently identified based on clinical guidelines. Model development for the POC assessment of a TC test was performed through three machine learning techniques: Support Vector Machine (SVM), Regularised Logistic Regression (RLR), and Random Forests (RF) along with a feature selection process. Disagreement in CVD risk predicted by LI and HI WHO/ISH models was 14.5% (n = 155; p<0.01) overall and comprised 36 clinically relevant T _HR patients (31% of patients identified as T _HR by using either model). Using two patient-specific parameters (age, systolic blood pressure), our POC assessment can pre-determine the benefit of TC testing and choose the appropriate risk model (out-of-sample AUCs:RF-0.85,SVM-0.84,RLR:0.82 and maximum sensitivity-98%). The identification of patients benefitting from a TC test for CVD risk stratification can aid planning for resource-allocation and save costs for large-scale screening programmes.