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High functional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography.

Hershberg R, Lipatov M, Small PM, Sheffer H, Niemann S, Homolka S, Roach JC, Kremer K, Petrov DA, Feldman MW, Gagneux S - PLoS Biol. (2008)

Bottom Line: We surveyed sequence diversity within a global collection of strains belonging to MTBC using seven megabase pairs of DNA sequence data.We show that the members of MTBC affecting humans are more genetically diverse than generally assumed, and that this diversity can be linked to human demographic and migratory events.We further demonstrate that these organisms are under extremely reduced purifying selection and that, as a result of increased genetic drift, much of this genetic diversity is likely to have functional consequences.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Stanford University, Stanford, California, USA.

ABSTRACT
Mycobacterium tuberculosis infects one third of the human world population and kills someone every 15 seconds. For more than a century, scientists and clinicians have been distinguishing between the human- and animal-adapted members of the M. tuberculosis complex (MTBC). However, all human-adapted strains of MTBC have traditionally been considered to be essentially identical. We surveyed sequence diversity within a global collection of strains belonging to MTBC using seven megabase pairs of DNA sequence data. We show that the members of MTBC affecting humans are more genetically diverse than generally assumed, and that this diversity can be linked to human demographic and migratory events. We further demonstrate that these organisms are under extremely reduced purifying selection and that, as a result of increased genetic drift, much of this genetic diversity is likely to have functional consequences. Our findings suggest that the current increases in human population, urbanization, and global travel, combined with the population genetic characteristics of M. tuberculosis described here, could contribute to the emergence and spread of drug-resistant tuberculosis.

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Related in: MedlinePlus

Correlations between Genetic and Geographic Distances in Ancient and Modern MTBC StrainsTo determine the route by which human-adapted MTBC strains were globally dispersed, we sought correlations between genetic and geographic distances in ancient (A) and modern (B) MTBC strains. The shortest distances between geographic locations via water routes (pink diamonds) or continental waypoints (i.e., land routes; blue squares) are plotted against the corresponding genetic distances expressed as the number of SNPs. In ancient strains, the correlation using either route was highly statistically significant (p < 0.0001 for both), but the correlation using land routes was slightly stronger. By contrast in modern strains the correlation using water routes was stronger and more statistically significant compared with land routes (p < 0.0001 and p = 0.05, respectively). Significant p values and r2 between 0 and 1 for all four analyses support the association between MTBC dispersal and human migration, which is consistent with early spread of MTBC out of Africa. The relative magnitude of r2 for land routes versus water routes suggests that spread of ancient strains occurred over land (i.e., through ancient human migration) and modern strains over water (i.e., through recent historical migration, trade, and conquest).
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pbio-0060311-g005: Correlations between Genetic and Geographic Distances in Ancient and Modern MTBC StrainsTo determine the route by which human-adapted MTBC strains were globally dispersed, we sought correlations between genetic and geographic distances in ancient (A) and modern (B) MTBC strains. The shortest distances between geographic locations via water routes (pink diamonds) or continental waypoints (i.e., land routes; blue squares) are plotted against the corresponding genetic distances expressed as the number of SNPs. In ancient strains, the correlation using either route was highly statistically significant (p < 0.0001 for both), but the correlation using land routes was slightly stronger. By contrast in modern strains the correlation using water routes was stronger and more statistically significant compared with land routes (p < 0.0001 and p = 0.05, respectively). Significant p values and r2 between 0 and 1 for all four analyses support the association between MTBC dispersal and human migration, which is consistent with early spread of MTBC out of Africa. The relative magnitude of r2 for land routes versus water routes suggests that spread of ancient strains occurred over land (i.e., through ancient human migration) and modern strains over water (i.e., through recent historical migration, trade, and conquest).

Mentions: The quantitative nature of our new diversity data permits a more rigorous analysis of this out-of-and-back-to-Africa hypothesis. Theory predicts that for an organism populating the world from a given point of origin, we will find a correlation between genetic variability and geographic distance traveled [59,60]. Thus, if our hypothesis is correct, we expect the genetic difference between any two strains to increase with geographic distance between where they originated. For all isolates, we used the haversine method with and without waypoints [59] to define pairwise distances over land routes and over water routes, respectively. Incorporation of waypoints into the calculation of geographic distances allows for the additional distances traveled via land routes during ancient human migrations. More direct geographic distances calculated without waypoints correspond to the water routes along which more recent human travel occurred once ocean-going ships became available. For each type of geographic distance, we computed the coefficient of linear correlation between geographic and genetic distances among ancient and modern strains, and tested its statistical significance. For all human-adapted MTBC strains we found a significant correlation between pairwise geographic and genetic distances, indicating that each group of strains carries a signal of the overall patterns of human demography and migration (Figure 5A and 5B). Furthermore, given the difference that we hypothesize between the migratory routes of ancient and modern strains we would expect that the correlation would be stronger for ancient strains spreading via land routes and for modern strains spreading via sea routes; this notion was supported by our statistical analysis (Figure 5A and 5B).


High functional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography.

Hershberg R, Lipatov M, Small PM, Sheffer H, Niemann S, Homolka S, Roach JC, Kremer K, Petrov DA, Feldman MW, Gagneux S - PLoS Biol. (2008)

Correlations between Genetic and Geographic Distances in Ancient and Modern MTBC StrainsTo determine the route by which human-adapted MTBC strains were globally dispersed, we sought correlations between genetic and geographic distances in ancient (A) and modern (B) MTBC strains. The shortest distances between geographic locations via water routes (pink diamonds) or continental waypoints (i.e., land routes; blue squares) are plotted against the corresponding genetic distances expressed as the number of SNPs. In ancient strains, the correlation using either route was highly statistically significant (p < 0.0001 for both), but the correlation using land routes was slightly stronger. By contrast in modern strains the correlation using water routes was stronger and more statistically significant compared with land routes (p < 0.0001 and p = 0.05, respectively). Significant p values and r2 between 0 and 1 for all four analyses support the association between MTBC dispersal and human migration, which is consistent with early spread of MTBC out of Africa. The relative magnitude of r2 for land routes versus water routes suggests that spread of ancient strains occurred over land (i.e., through ancient human migration) and modern strains over water (i.e., through recent historical migration, trade, and conquest).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2602723&req=5

pbio-0060311-g005: Correlations between Genetic and Geographic Distances in Ancient and Modern MTBC StrainsTo determine the route by which human-adapted MTBC strains were globally dispersed, we sought correlations between genetic and geographic distances in ancient (A) and modern (B) MTBC strains. The shortest distances between geographic locations via water routes (pink diamonds) or continental waypoints (i.e., land routes; blue squares) are plotted against the corresponding genetic distances expressed as the number of SNPs. In ancient strains, the correlation using either route was highly statistically significant (p < 0.0001 for both), but the correlation using land routes was slightly stronger. By contrast in modern strains the correlation using water routes was stronger and more statistically significant compared with land routes (p < 0.0001 and p = 0.05, respectively). Significant p values and r2 between 0 and 1 for all four analyses support the association between MTBC dispersal and human migration, which is consistent with early spread of MTBC out of Africa. The relative magnitude of r2 for land routes versus water routes suggests that spread of ancient strains occurred over land (i.e., through ancient human migration) and modern strains over water (i.e., through recent historical migration, trade, and conquest).
Mentions: The quantitative nature of our new diversity data permits a more rigorous analysis of this out-of-and-back-to-Africa hypothesis. Theory predicts that for an organism populating the world from a given point of origin, we will find a correlation between genetic variability and geographic distance traveled [59,60]. Thus, if our hypothesis is correct, we expect the genetic difference between any two strains to increase with geographic distance between where they originated. For all isolates, we used the haversine method with and without waypoints [59] to define pairwise distances over land routes and over water routes, respectively. Incorporation of waypoints into the calculation of geographic distances allows for the additional distances traveled via land routes during ancient human migrations. More direct geographic distances calculated without waypoints correspond to the water routes along which more recent human travel occurred once ocean-going ships became available. For each type of geographic distance, we computed the coefficient of linear correlation between geographic and genetic distances among ancient and modern strains, and tested its statistical significance. For all human-adapted MTBC strains we found a significant correlation between pairwise geographic and genetic distances, indicating that each group of strains carries a signal of the overall patterns of human demography and migration (Figure 5A and 5B). Furthermore, given the difference that we hypothesize between the migratory routes of ancient and modern strains we would expect that the correlation would be stronger for ancient strains spreading via land routes and for modern strains spreading via sea routes; this notion was supported by our statistical analysis (Figure 5A and 5B).

Bottom Line: We surveyed sequence diversity within a global collection of strains belonging to MTBC using seven megabase pairs of DNA sequence data.We show that the members of MTBC affecting humans are more genetically diverse than generally assumed, and that this diversity can be linked to human demographic and migratory events.We further demonstrate that these organisms are under extremely reduced purifying selection and that, as a result of increased genetic drift, much of this genetic diversity is likely to have functional consequences.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Stanford University, Stanford, California, USA.

ABSTRACT
Mycobacterium tuberculosis infects one third of the human world population and kills someone every 15 seconds. For more than a century, scientists and clinicians have been distinguishing between the human- and animal-adapted members of the M. tuberculosis complex (MTBC). However, all human-adapted strains of MTBC have traditionally been considered to be essentially identical. We surveyed sequence diversity within a global collection of strains belonging to MTBC using seven megabase pairs of DNA sequence data. We show that the members of MTBC affecting humans are more genetically diverse than generally assumed, and that this diversity can be linked to human demographic and migratory events. We further demonstrate that these organisms are under extremely reduced purifying selection and that, as a result of increased genetic drift, much of this genetic diversity is likely to have functional consequences. Our findings suggest that the current increases in human population, urbanization, and global travel, combined with the population genetic characteristics of M. tuberculosis described here, could contribute to the emergence and spread of drug-resistant tuberculosis.

Show MeSH
Related in: MedlinePlus