Population Migration and the Variation of Dopamine D4 Receptor (DRD4) Allele Frequencies Around the Globe Moira Maxwell

Dopamine The neurotransmitter dopamine plays a huge role in the body, and has been implicated in ADHD D4 is a dopamine receptor gene that has 2-11 repeat units. DRD4 in humans is linked to: Novelty-seeking Hyperactivity Risk-taking behaviors These are typical ADHD behaviors Consistent with findings in animal studies: Increase in exploratory behavior Increase in speed and locomotion These behaviors are adaptive for maximizing resources in a new environment

Hypotheses Populations with a history of migration in the past 1,000 - 30,000 years will show high rates of DRD4 alleles. Macro-migration: Populations that have migrated many thousands of miles will show a higher rate of DRD4 alleles than populations who have not migrated as far. Micro-migration: Populations that use sedentary subsistence strategies will have a lower percentage of DRD4 alleles than nomadic populations.

Methods 12 studies with a total sample size of 2,320 individuals with no psychiatric disorders from 39 countries were analyzed. 4,640 alleles looking for the proportion of 7-repeats the proportion of long alleles as an index of genotype in a population

Macro-migration Estimated in thousands of miles (kmiles) of population from homeland of its language family. Based on the archeological record and historical linguistics Macro-migrations occured 1,000-30,000 years ago

6 Main Migration Routes American Indians- NE Asia>North America>Central and South America China>Japan/Taiwan/SE Asia/The Pacific Jews>Ethiopia/Yemen/Europe West Africa>Central/Eastern/Southern Africa Black Sea>Europe(Indio Europeans) Melanesians>SE Asia

Table 2 (highlight muskoke, guahibo, ticuna, roman jews, malay, bantu, swedes

Macro-migration hypothesis A strong correlation of r =.85 (p<.001) was found between kmi traveled and DRD4 long allele frequency distributions Supports hypothesis for macro-migration used a solid p-value

Fig 1 C. Chen et al. of correlations. A more accurate view is that autocorrelation increases the variance

Micro-Migration Measures survival strategies used by the 39 societies in this analysis. Societies were coded as either sedentary=0 (28 societies) or as nomadic=1 (11 societies) Nomadic populations had a 10.4% higher rate of DRD4 long alleles than sedentary ones.

Micro-migration hypothesis A correlation of r =.52 (p<.001) was found between percentage of long alleles and subsistence type in a population Supports hypothesis for micro-migration

Macro and micro-migration Correlation of macro and micro-migration was r =.39 (p<.05) Regression analysis showed that macro-migration was a better indicator of DRD4 allele frequency than micro-migration For every kmi away from homeland, the proportion of DRD4 long alleles increased by 4.3%

The confound of Auto-correlation Occurs when sampling units are not independent Leads to Type I error (rejecting null when it is actually true) All societies in this study have had contact with other societies, making it hard to discern if there is an effect of auto-correlation or not. This is particularly true of American Indians who are known to share common ancestry with each other. Researchers corrected for this by including all available data in order to increase sample size After correction, hypothesis for macro-migration was still supported, but not as strongly for micro-migration as p-value dropped from p<.001 to p<.11

Does the bottleneck effect explain the results? Populations that are isolated after migration experience a bottleneck effect because of a limited gene pool. None of the other 128 alleles examined followed the migratory patterns of the populations

DRD4 allele frequency and migration Correlation found? Yes Causation? Three competing hypotheses “Founder’s effects” or “Natural selection/deselection” Spontaneous mutation - can rule this out because r is too high to be by chance

Founder’s effects hypothesis Populations migrated because of the genetic makeup of their members More long alleles in population would increase exploratory behavior which may increase group migration DRD4 allele frequencies seen in early populations would be the same in modern populations

Natural selection / deselection Forced migration due to War Depletion of natural resources causing famine Natural selection in populations that adapted to multiple migrations would cause an increase of DRD4 genes In sedentary populations, lack of migration would cause a deselection of DRD4 long alleles.

How to test Ideal solution: Compare genetic data from populations that is at least 15,000 years old (pre-agriculture) and compare that with modern genetic data on frequency of DRD4 alleles. This is not possible yet, so the authors chose the proximate mechanism of testing DRD4 frequency in modern day immigrants and in their counterparts remaining in country of origin.

Table 3

Results Table 3 shows a lack of support for the “Founder’s effects” hypothesis as DRD4 frequency rates are the same for immigrants and non-immigrants Founder’s hypothesis and NS/dS hypothesis are competing, so therefore the “Natural selection/deselection” hypothesis is supported.

Natural selection/deselection Humans began as nomadic foragers who migrated away from their places of origin repeatedly. Researchers believe there would have been strong pressure to select for genes that favored exploratory behaviors. Repeated migrations would continue to increase the frequency of these genes. ~15,000 years ago humans began to use agriculture rather than hunter-gathering. Populations who did not migrate far after agriculture would have deselected for migratory genes. Deselection appears to explain the effects micro-migration on DRD4 frequencies.

ADHD Thought to be a result of selective pressures on migratory behaviors. Very adaptive then, but not in our (almost) exclusively sedentary modern societies. Evolutionary time-lag: If society persists as sedentary for long enough, a decrease in ADHD will be seen as it will no longer be adaptive.

Further testing Testing on non-human primates Are there high rates of DRD4 long alleles in other populations with macro-migration?

Global rates of ADHD Worldwide rate of ADHD is 5.2% (Polanczyk et. al, 2007) “The North American rate (6.2%) only slightly exceeded the European rate (4.6%). The highest rates emerged from Africa (8.5%) and South America (11.8%). Corroboration comes from a dimensional ADHD scale used in 21 countries. Japanese and Finnish children scored lowest, Jamaican and Thai children scored highest, and American children scored about average.” (Moffitt and Melchior, 2007)