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PubMed1994

A combined test of linkage heterogeneity.

This paper focuses on the problem of testing for heterogeneity once linkage is established. In an investigation of genetic linkage, Morton first proposed a general purpose test to detect heterogeneity in the recombination fraction. Two more commonly used tests of linkage heterogeneity are the admixture test (A-test) of Smith, Ott, and Risch and Baron, and the B-test of Risch. All are likelihood-ratio tests, but they differ in the models specifying the heterogeneity. A new test of heterogeneity in the presence of linkage is presented here. I propose a mixture model of heterogeneity, which allows the recombination fraction to vary among families, as does the B-model, yet also allows some families to be unlinked, as the A-model does. This model contains the A and B models as special cases and thus allows a direct test (D-test), which can provide justification for choosing one of these extremes.

Family↗
PubMed1994

Impact of heterogeneity in the predictive value of kinetic parameters in canine osteosarcoma.

Intratumoral heterogeneity has been identified as a potential problem in the efficacy of predictive assays. Canine osteosarcoma is an extremely heterogeneous solid tumor that has been shown to be an excellent model for the human disease. Intratumoral heterogeneity of kinetic parameters and the effect of heterogeneity on predicting outcome of treatment (time until metastasis) were studied in dogs with naturally occurring osteosarcoma. Dogs were treated with amputation or tumor excision and limb-sparing followed by chemotherapy with cisplatin. Kinetic parameters evaluated included v, duration of DNA synthesis (Ts), and potential doubling time (Tpot), determined using in vivo labeling with bromodeoxyuridine and flow cytometry. In 30 tumors, multiple samples were obtained and evaluated. There was significantly more variation between tumors from different dogs than intratumoral variation of v, Ts, and Tpo. Variations in v, Ts, and Tpot within a tumor were associated with both sample location and tumor subpopulation. Time to metastasis was determined in 51 dogs with tumors sampled for kinetics. Multiple samples were available from 25 of these tumors. Cox proportional hazard analysis was performed using either the fastest or slowest Tpot from each sample. The fastest available Tpots were highly significant (P < 0.001) for prediction of outcome. The slowest available Tpots were also significant predictors, although the statistical strength was compromised (P = 0.024). Obtaining at least two samples in large tumors known to be heterogeneous is recommended to improve the predictive ability of Tpot. v is a more limited predictor but can useful when Tpot is not available. In canine osteosarcoma, an extremely heterogeneous tumor, kinetic parameters were shown to be predictors of outcome.

Animals↗
PubMed1993

Monoclonal c-myc transformed macrophage cell lines. I. Heterogeneity in ability to process and present antigen.

Processing of proteins into immunogenic forms and their subsequent presentation to T cells are mediated by APC. Monocytes and macrophages have long been recognized as one of the APC types. However, little is known about whether functional heterogeneity in processing and presentation exist within the monocyte/macrophage population. Past difficulties in obtaining clonal representatives of these populations have limited investigations in this regard. The c-myc-containing retrovirus MRV, previously shown to immortalize murine macrophages, was used to generate a large panel of macrophage cell clones. Differences observed in cell surface antigen expression and morphology demonstrated phenotypic heterogeneity among these clones. Functional heterogeneity was also observed both before and after IFN-gamma and IL-4 stimulation. The clones differ in their capacity to present several nominal antigens to T cell hybridomas. When parallel variation in ability to present both a nominal antigen and a peptide representing the epitope for which a T cell hybridoma was specific was observed among the clones, this variation correlated with the levels of surface MHC class II antigen the clones expressed. In contrast, diversity in the ability to process and present certain nominal antigens among clones that all presented the corresponding antigenic peptide with similar efficiency did not appear to be due to differences in levels of surface MHC class II molecules. Our results suggest that the macrophage clones are heterogeneous in their ability to both process and present several antigens. The ability to obtain macrophage tissue culture cell lines displaying phenotypic and functional heterogeneity should allow insight into the impact of normal macrophage heterogeneity on the outcome of immune responses in vivo.

Animals↗
PubMed1994

[DNA heterogeneity and its significance in colon carcinoma].

We performed DNA flow cytometry analysis of colon carcinomas from the viewpoint of DNA heterogeneity. The materials were 25 colon carcinomas and 17 metastatic lymph nodes. Four different regions were examined in each primary tumor. The DNA index (DI) was classified into four groups. We classified the primary tumors into homogeneous and heterogeneous group according to the DI of the four regions of each case. Ten of 25 (40%) were classified as homogeneous and 15 (60%) as heterogeneous. The heterogeneous group tended to show more aggressive clinicopathologic characteristics. The corresponding rate between the maximum DI in the primary tumor and the DI in the metastatic lymph node was 65% (11/17). The maximum DI of the primary tumors was mostly seen in the metastatic lymph nodes, suggesting high metastatic potentiality of the higher DI clones. The examination of DNA heterogeneity may be useful for detecting the more precise character of the colon carcinomas. In heterogeneous cases, the higher corresponding rate of DI between primary and metastatic lesions suggested that metastasis occurred frequently in primary lesions containing gathering larger DI cells.

Adenocarcinoma↗
PubMed1994

[DNA heterogeneity in oral cavity and hypopharyngeal carcinoma].

The study was carried out on 18 cases of oral cavity carcinoma and 12 cases of hypopharyngeal carcinoma to assess the degree of intratumoral heterogeneity and the relation to tumor size, lymph metastasis and histological type. In oral cavity carcinoma, 6 cases (33%) were aneuploid, while in hypopharyngeal carcinoma all were aneuploid. DNA heterogeneity was identified in 4 cases (22%) in oral cavity carcinoma, end in 6 cases (50%) of hypopharyngeal carcinoma. No correlation was found between DNA heterogeneity and tumor size, lymph metastasis and histological type. However, even early carcinomas have intratumoral DNA heterogeneity. It was supposed that the result which hypopharyngeal carcinoma had higher degree of aneuploid and DNA heterogeneity comparing with oral cavity carcinoma supported that hypopharyngeal carcinoma had higher clinical malignancy from the aspect of proliferative movement. The data indicate that it is impossible to analyze correct DNA content by only one specimen and it is important to investigate intratumoral DNA heterogeneity to research the mechanism of multiplicity and clinical malignancy of carcinoma.

Adult↗
PubMed1997

Defining etiologic heterogeneity in breast cancer using genetic biomarkers.

Most breast cancer has a complex, multifactorial etiology. One consequence of this multifactorial phenomenon is that etiological heterogeneity may exist. This heterogeneity implies simply that two or more groups of breast cancer cases in the general population may have been caused by different sets of events. The ability to define etiologically heterogeneous subgroups in the population may facilitate a number of research and clinical issues. Studying etiologically homogeneous subgroups in the general population may improve the ability to identify etiologic agents. Identification of a homogeneous group of breast cancer cases may also aid breast cancer diagnosis or treatment, and may allow a more effectively application of cancer prevention and control strategies. Defining etiologic heterogeneity in the general population is one initial step in the process of understanding cancer etiology. Using knowledge such as that provided in the two examples presented here, formal case-control or cohort studies can be undertaken to examine whether the factors that define etiologic heterogeneity are involved in etiology. Furthermore, the results of studies of etiologic heterogeneity can point toward potential gene-gene or gene-environment interactions. The type of studies presented here can therefore serve a useful role in leading to more formal molecular epidemiological analyses.

Age of Onset↗
PubMed1998

A mathematical model for the heterogeneity of myocardial perfusion using nitrogen-13-ammonia.

UNLABELLED: Heterogeneity of left ventricular myocardial perfusion is an important clinical characteristic. Different aspects of this heterogeneity were analyzed. METHODS: The coefficient of variation (v), characterizing heterogeneity, was modeled as a function of the number of segments (n), characterizing spatial resolution of the measurement, using two independent pairs of mutually dependent parameters: the first pair describes v as a power function of n, and the second pair adds a correction for n small. n was varied by joining equal numbers of neighboring segments. Local similarity of the perfusion was characterized by the correlation between the perfusions of neighboring segments. Genesis of the perfusion distribution was modeled by repeated asymmetric subdivision of the perfusion into a volume among two equal subvolumes. These analyses were applied to study the differences between 16 syndrome X patients and 16 age- and sex-matched healthy volunteers using 13N-ammonia parametric PET perfusion data with a spatial resolution of 480 segments. RESULTS: The heterogeneity of patients is higher for the whole range of spatial resolutions considered (2 < or = n < or = 480; for n = 480, v = 0.22 +/- 0.03 and 0.18 +/- 0.02; p < 0.005). This is because the first pair of parameters differs between patients and volunteers (p < 0.005), whereas the second pair does not (p > 0.1). For both groups of subjects there is a significant positive local correlation for distances up to 30 segments. This correlation is a formal description of the patchy nature of the perfusion distribution. CONCLUSION: When comparing values of v, these should be based on the same value of n. The model makes it possible to calculate v for all values of n < or = 480. Mean perfusion together with the two pairs of parameters are necessary and sufficient to describe all aspects of the perfusion distribution. For n small, heterogeneity estimation is less reliable. Patients have a higher heterogeneity because their perfusion distribution is more asymmetrical from the third to the seventh generation of subdivision (8 < or = n < or = 128). Therefore, a spatial resolution of n > or = 128 is recommended for parametric imaging of perfusion with PET. Patients have only a very slightly more patchy distribution than volunteers. The differences in perfusion between areas with low perfusion and areas with high perfusion is larger in patients.

Ammonia↗
PubMed1996

Clinical implications of viral quasispecies heterogeneity in chronic hepatitis C.

To determine the clinical significance of viral quasispecies heterogeneity, 59 patients with chronic hepatitis C were studied using singlestranded conformational polymorphism (SSCP) analysis of the HCV E2 hypervariable region 1 (HVR1); of these, 48 were subsequently treated with interferon-alpha. The SSCP method was validated using clones of known nucleotide sequence. HVR1 was amplified in 54 of 59 (92%) patients. The median number of SSCP bands per sample was 6 (range: 2-12). Increased quasispecies heterogeneity correlated with the estimated duration of HCV infection (P < 0.05), parenteral-acquired HCV infection (vs. sporadic, P < 0.05), serum HCV RNA levels (P < 0.05), and HCV genotype 1 infection (P < 0.05), but not with age, serum AST, ALT, or Knodell score. Patients who had complete and sustained response to interferon-alpha (n = 11) had lower pre-treatment quasispecies heterogeneity compared to patients who had complete response with relapse (n = 18, P < 0.05) or no complete response (n = 16, P < 0.01). However, multivariate analysis revealed that HCV viremia was a stronger predictor of response to interferon-alpha. These findings indicate that the estimated duration of HCV carriage, serum HCV RNA levels, and HCV type 1 are important determinants for the evolution of HCV quasispecies heterogeneity; and that increased HCV quasispecies heterogeneity is another marker associated with a poor subsequent response to interferon-alpha.

Adult↗
PubMed1996

Heterogeneity of familial risk in sarcoidosis.

Familial clustering of sarcoidosis and the higher prevalence and clinical severity of sarcoidosis in African Americans suggests etiologic heterogeneity. To test for heterogeneity in familial risk of sarcoidosis, we studied 3,395 siblings and parents of 558 index cases (361 African American, 197 Caucasian) diagnosed at Henry Ford Hospital between 1951 and 1994. Using the age- and sex-specific cumulative incidence of sarcoidosis in our sample, we found a statistically significant heterogeneity in familial risk of disease (P < .001). To determine if this was due to a greater risk of sarcoidosis in African Americans, we recalculated disease probabilities using age-, sex-, and race-specific disease cumulative incidence and found the same amount of heterogeneity in familial risk (P < .001). Index cases (n = 69) from high-risk families were more likely to be African American (odds ratio [OR] = 3.24; 95% confidence interval (CI) = 1.71-6.14) and to have an offspring or second- degree relative affected (OR = 6.21; 95% CI = 2.86-13.45). We conclude that the heterogeneity of familial sarcoidosis risk found in this study is supportive of multiple etiologies. Our results also show that a quantitative assessment of familial risk based on siblings and parents may be a useful screening tool for identifying families with additional affected members. Of the high-risk families, African Americans made up a greater-than-expected percentage even after accounting for differences in disease prevalence. We suggest targeting African Americans for studies of sarcoidosis that focus on Mendelian hypotheses and genetic linkage.

Adult↗
PubMed2001

Heterogeneous distribution of P53 immunoreactivity in human lung adenocarcinoma correlates with MDM2 protein expression, rather than with P53 gene mutation.

Although the tumor suppressor p53 protein (P53) immunoreactivity and its gene (p53) mutation were reported to be significant prognostic indicators for human lung adenocarcinomas, little is known regarding the relationship between the heterogeneous distribution of P53 and its genetic status in each tumor focus and the clinicopathological significance. To determine how P53 is heterogeneously stabilized in patients, we compared P53 expression to both the p53 allelic mutation in exon 2 approximately 9 by polymerase chain reaction-single strand conformation polymorphism using microdissected DNA fractions, and the immunohistochemical MDM2 expression. Of the 48 positive to P53 in 118 lung adenocarcinomas examined, 10 with heterogeneous P53 expression were closely examined. The higher P53 expression foci in 7 of 10 cases were less differentiated, histologically in respective cases, and were frequently associated with fibrous stroma. Two had genetic mutations in exon 7 of the p53 gene in both the high and low P53 expression foci of cancer tissue indicating no apparent correlation between heterogeneous P53 expression and the occurrence of gene mutation. Immunohistochemical expression of MDM2 was significantly lower in high P53 expression areas (p < 0.05, the mean labeling indices of high and low P53 expression areas being 4.2 +/- 5.4% and 13.6 +/- 12.2%, respectively). In addition, among all the 118 cases examined, MDM2 expression was significantly suppressed in cases of p53 gene mutation, simultaneously with P53 overexpression, as compared with cases without both the p53 mutation and expression (p < 0.001). These findings suggest that the heterogeneous stabilization of P53 in human lung adenocarcinomas could be partly due to suppressed MDM2 expression. The overexpression of non-mutated P53 may afford a protective mechanism in human lung adenocarcinomas.

Adenocarcinoma↗
PubMed1996

Evidence of genetic heterogeneity of Leber's congenital amaurosis (LCA) and mapping of LCA1 to chromosome 17p13.

Leber's congenital amaurosis (LCA) is an autosomal recessive disease responsible for congenital blindness. It is the earliest and most severe inherited retinal dystrophy in human and its genetic heterogeneity has long been recognised. We have recently reported on the first localisation of a disease gene (LCA1) to the short arm of chromosome 17 by homozygosity mapping in five families of North African origin. Here, we refine the genetic mapping of LCA1 to chromosome 17p13 between loci D17S938 and D17S1353 and provide strong support for the genetic heterogeneity of this condition (maximum likelihood for heterogeneity, 17.20 in InL; heterogeneity versus homogeneity, P = 0.0002, heterogeneity versus no linkage, P < 0.0001)

Blindness↗
PubMed2026

Multiregion profiling of genomic and transcriptional heterogeneity in head and neck squamous-cell carcinoma.

BACKGROUND: Intratumoral heterogeneity (ITH) is thought to contribute to tumour evolution and treatment resistance but its biological and clinical significance in localised head and neck squamous-cell carcinoma (HNSCC) remains incompletely understood. PATIENTS AND METHODS: In the prospective SCANDARE study, we analysed 87 patients with resectable HNSCC treated with upfront surgery. Two to five spatially distinct tumour regions per patient underwent pathological evaluation, targeted DNA sequencing, and bulk RNA sequencing. Genomic ITH (gITH) was quantified using clonal deconvolution and Shannon diversity indices, whereas transcriptional heterogeneity (tITH) was assessed using the intratumour expression distance metric. Associations between ITH, molecular features, tumour microenvironment composition, and clinical outcomes were explored using multivariable statistical models. RESULTS: Pathology-based spatial heterogeneity showed limited prognostic value. gITH was common, with 37% of tumours displaying regionally heterogeneous pathogenic variants, including spatially actionable alterations in 10% of patients. In an initial multivariable Cox model, higher gITH was associated with shorter disease-free survival. However, after Ridge-penalised modelling and bootstrap internal validation, the effect size was attenuated [corrected hazard ratio 1.42, 95% confidence interval (CI) 0.91-2.75]. The overall model retained moderate discriminative performance (optimism-corrected C-index 0.69, 95% CI 0.59-0.79). gITH was associated with tumour cellularity, reduced estimated endothelial cell infiltration, and alterations in KMT2C and PIK3CA. tITH differed according to human papillomavirus (HPV) status, with lower tITH in HPV-positive tumours, and was associated with distinct biological pathways and genomic alterations. Genomic and tITH were not correlated. CONCLUSIONS: This prospective multiregion study provides a comprehensive characterisation of genomic and tITH in localised HNSCC. Our findings highlight substantial spatial molecular diversity within primary tumours and suggest potential associations between heterogeneity, tumour biology, and clinical outcome that warrant validation in independent cohorts.

head and neck squamous-cell carcinoma (HNSCC)↗
PubMed2005

Heterogeneity, histological features and DNA ploidy in oral carcinoma by image-based analysis.

Oral squamous carcinomas appear heterogeneous on DNA ploidy analysis. However, this may be partly a result of sample dilution or the detection limit of techniques. The aim of this study was to determine whether oral squamous carcinomas are heterogeneous for ploidy status using image-based ploidy analysis and to determine whether ploidy status correlates with histological parameters. Multiple samples from 42 oral squamous carcinomas were analysed for DNA ploidy using an image-based system and scored for histological parameters. 22 were uniformly aneuploid, 1 uniformly tetraploid and 3 uniformly diploid. 16 appeared heterogeneous but only 8 appeared to be genuinely heterogeneous when minor ploidy histogram peaks were taken into account. Ploidy was closely related to nuclear pleomorphism but not differentiation. Sample variation, detection limits and diagnostic criteria account for much of the ploidy heterogeneity observed. Confident diagnosis of diploid status in an oral squamous cell carcinoma requires a minimum of 5 samples.

Carcinoma, Squamous Cell↗
PubMed1999

Translation-coupled violation of Parity Rule 2 in human genes is not the cause of heterogeneity of the DNA G+C content of third codon position.

The genome of higher eukaryotes consists of genes having a widely heterogeneous base composition at the third codon position. Ubiquitous variability of the DNA base composition has the following two aspects: intragenomic heterogeneity of the G+C content and the amino-acid-specific translation-coupled biases from the Parity Rule 2 (PR2). PR2 is an intrastrand rule where A = T and G = C are expected if there is no bias in mutation and selection between the two complementary strands of DNA. To examine whether or not the biases from PR2 are responsible for the wide heterogeneity of the DNA G+C content in human, the third codon position of 846 human genes was analyzed. Genes were separated into six groups according to their G+C content of the third codon position, and each group was examined for the translation-coupled PR2 biases in the nucleotide composition of the third codon position for two- and four-codon amino acids. The results show that genes in the different G+C content groups have similar PR2 biases, indicating that the intragenomic heterogeneity of the G+C content is not correlated with translation-coupled biases from the PR2. Therefore, the heterogeneity of the G+C content is likely to be determined by some other mechanism (e.g. locally variable directional mutation pressures) than amino-acid-specific selections for the codon preference.

Base Composition↗
PubMed2001

Heterogeneity of stress gene expression and stress resistance among individual cells of Saccharomyces cerevisiae.

Knowledge of gene expression and cellular responses in microorganisms is derived from analyses of populations consisting of millions of cells. Analytical techniques that provide data as population averages fail to inform of culture heterogeneity. Flow cytometry and fluorescence techniques were used to provide information on the heterogeneity of stress-responsive gene expression and stress tolerance in individual cells within populations. A sequence of DNA encoding the heat shock and stress response elements of the Saccharomyces cerevisiae HSP104 gene was used to express enhanced green fluorescent protein (EGFP). When integrated into the genome of yeast strain W303-1A, intrinsic expression of EGFP increased about twofold as cells progressed from growth on glucose to ethanol utilization in aerobic batch cultures. Staining of cells with orange/red fluorescent propidium iodide (PI), which only enters cells that have compromised membrane integrity, revealed that the population became more tolerant to 52 degrees C heat stress as it progressed from growth on glucose and through the ethanol utilization phase of aerobic batch culture. Exposure of cultures growing on glucose to a mild heat shock (shift from 25 degrees C to 37 degrees C) resulted in significantly increased expression of EGFP in the population. However, there was heterogeneity in the intensity of fluorescence of individual cells from heat-shocked cultures, indicating variability in the strength of stress response in the clonal population. Detailed analysis of the heterogeneity showed a clear positive trend between intensity of stress response and individual cell resistance, measured in terms of PI exclusion, to heat stress at 52 degrees C. Further experiments indicated that, although the mean gene expression by a population is influenced by the genetic background, the heterogeneity among individual cells in clonal populations is largely physiologically based.

Base Sequence↗
PubMed2025

Unveiling non-small cell lung cancer treatment effect heterogeneity: a comparative analysis of statistical methods.

BACKGROUND: For patients with advanced non-small cell lung cancer lacking targetable genomic alterations, the impact of clinicogenomic characteristics on the effectiveness of combining chemotherapy with immunotherapy is unclear. METHODS: We evaluated 4 statistical methods for detecting heterogeneous treatment effects related to clinical factors, including programmed death-ligand 1 expression, tumor mutation burden, and stage at diagnosis, using the American Association for Cancer Research Project Genomics Evidence Neoplasia Exchange BioPharma Collaborative dataset supplemented with institutional data collected under the same data curation model. A 2-sided P value of no more than .05 was used to denote statistical significance for all analyses. RESULTS: The mixture model revealed 2 latent subgroups: in one subgroup, there was no meaningful treatment effect, with average progression-free survival (PFS) only 5% longer with immunotherapy alone (95% confidence interval [CI] = -19% to 35%); in the second subgroup, immunotherapy alone was associated with a 35% decrease in average PFS (95% CI = -59% to 2%), corresponding to a ratio in treatment effects of 1.62 (95% CI = 1.02 to 2.57). There was a marginal association between lower tumor mutation burden levels and membership in the subgroup with improved PFS following receipt of chemoimmunotherapy. The causal survival forest highlighted the importance of tumor mutation burden (variable importance ranking: 1) and programmed death-ligand 1 (variable importance ranking: 3) when assessing heterogeneity. In contrast, the accelerated failure time and Cox proportional hazards models did not detect any statistically significant heterogeneous treatment effects. In simulations, the mixture model identified heterogeneous treatment effects more frequently than other methods, especially with weak covariate relationships, demonstrating its utility for informing personalized treatment approaches. CONCLUSIONS: The application of novel statistical methods to large scale clinico-genomic databases offers an opportunity to more accurately identify heterogeneous treatment effects in some settings as compared to traditional statistical methods. Applying such methods to the AACR Project GENIE BPC non-small cell lung cancer data indicated a potential association between decreasing tumor mutation burden and improved outcomes with chemoimmunotherapy as compared to immunotherapy alone.

Humans↗
PubMed2003

Heterogeneity of nucleotide frequencies among evolutionary lineages and phylogenetic inference.

A major assumption of many molecular phylogenetic methods is the homogeneity of nucleotide frequencies among taxa, which refers to the equality of the nucleotide frequency bias among species. Changes in nucleotide frequency among different lineages in a data set are thought to lead to erroneous phylogenetic inference because unrelated clades may appear similar because of evolutionarily unrelated similarities in nucleotide frequencies. We tested the effects of the heterogeneity of nucleotide frequency bias on phylogenetic inference, along with the interaction between this heterogeneity and stratified taxon sampling, by means of computer simulations using evolutionary parameters derived from genomic databases. We found that the phylogenetic trees inferred from data sets simulated under realistic, observed levels of heterogeneity for mammalian genes were reconstructed with accuracy comparable to those simulated with homogeneous nucleotide frequencies; the results hold for Neighbor-Joining, minimum evolution, maximum parsimony, and maximum-likelihood methods. The LogDet distance method, specifically designed to deal with heterogeneous nucleotide frequencies, does not perform better than distance methods that assume substitution pattern homogeneity among sequences. In these specific simulation conditions, we did not find a significant interaction between phylogenetic accuracy and substitution pattern heterogeneity among lineages, even when the taxon sampling is increased.

Algorithms↗
PubMed2006

Regional heterogeneity and gene flow maintain variance in a quantitative trait within populations of lodgepole pine.

Genetic variation is of fundamental importance to biological evolution, yet we still know very little about how it is maintained in nature. Because many species inhabit heterogeneous environments and have pronounced local adaptations, gene flow between differently adapted populations may be a persistent source of genetic variation within populations. If this migration-selection balance is biologically important then there should be strong correlations between genetic variance within populations and the amount of heterogeneity in the environment surrounding them. Here, we use data from a long-term study of 142 populations of lodgepole pine (Pinus contorta) to compare levels of genetic variation in growth response with measures of climatic heterogeneity in the surrounding region. We find that regional heterogeneity explains at least 20% of the variation in genetic variance, suggesting that gene flow and heterogeneous selection may play an important role in maintaining the high levels of genetic variation found within natural populations.

Climate↗