200 Years After Darwin

Abstract

ON FEBRUARY 12, 2009, WE CELEBRATE THE 200TH anniversary of the birth of Charles Darwin. He has earned the scientific reputation as being the most influential naturalist-biologist of his generation and perhaps of all time. Achievement of his esteemed status resulted initially from studying the geographical distribution of wildlife and fossils collected on his 5-year voyage on the Beagle and concluding that the “transmutation of species” was due to natural selection. In 1858, he was in the process of documenting his research when he received an essay from Alfred Russel Wallace putting forth the same concept of natural selection as the mechanism for generation of new species, resulting in a joint publication that same year. On the Origin of Species was published by Darwin in 1859, making it now the 150th anniversary of its publication. This book proposed evolution as the scientific basis of diversity and species generation produced through the effects of natural selection. Evolution has been proven to be the mechanism for species generation and the engine for change is natural selection, providing the evolved species, beginning from a common organism, adaptation and fitness to maximize reproduction and survival. Dobzhansky put it succinctly by saying that “nothing in biology makes sense except in the light of evolution.” Darwin expressed it eloquently in 1859: There is grandeur in this view of life, with its several powers, having been originally breathed into a few forms or into one; and that, whilst this planet has gone cycling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being evolved. Two hundred years after Darwin’s birth, molecular genomic analyses of the human genome have been implemented, seeking the genetic basis for natural selection providing biological fitness and also risk of developing disease. Genome-wide association studies (GWASs) seeking gene variations, or single-nucleotide polymorphisms (SNPs), causal of several human diseases have been conducted in recent years. These diseases include autism, schizophrenia, obesity, diabetes, and heart disease. Several GWASs for risk association with neurological diseases,orneuromicstudies,havebeenreported. Increasedrisks foramyotrophic lateral sclerosis,Alzheimerdisease(AD), restless legssyndrome,andmultiplesclerosishavebeenassociated with polymorphisms in specific genes. It was hoped that these observationswouldadvanceanunderstandingof thecausation of inherited, complexpolygenetic,multifactorialneurological diseases. They have been made possible by the publication of thehumangenomeandhaplotypestudies (HapMapanalyses). Awhole-genomeanalysisofsporadicamyotrophiclateralsclerosis was published by Dunckley et al. They identified 10 genetic loci that were associated with sporadic amyotrophic lateral sclerosis in 3 independent series of patients and control subjects.Themostsignificantassociationwithdiseasewasfound foraSNPnearanuncharacterizedgeneknownasFLJ10986on chromosome1.Thus, theydescribedspecificSNPs that areassociated with onset of sporadic amyotrophic lateral sclerosis. Reiman et al conducted a genome-wide survey of 502 627 SNPs to characterize and confirm late-onset AD susceptibility genes. They found that late-onset AD was associated with 6 SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. The GAB2 gene was overexpressed in pathologically vulnerable neurons, and interference with GAB2 gene expression increased tau phosphorylation. They concluded that GAB2 modifies late-onset AD risk in apolipoprotein E (APOE) e4 allele carriers. Coon et al found a single SNP in linkage disequilibrium to the APOE e4 allele in a neurome-wide association study. Grupe et al described 3 additional SNPs on chromosome 19 in linkage disequilibrium to the APOE e4 locus also in a neurome-wide association study. Liu et al described significant linkage to 3q23 markers associated with AD in a genetically isolated Dutch population. In 2008, Li et al described SNPs associated with risk and ageatonsetofADinaGWASof469 438SNPs.They identified theAPOE linkagedisequilibriumregionasthestrongestgenetic risk factor for AD. They concluded that this event could be a consequence of the coevolution of more than 1 susceptibility allele, includingAPOC1, inthesameregion.Additionalpotential at-riskgenes forADwereof interestandrequire furtherstudies.