disease

Here's an interesting abstract from a 2005 review paper by Ann Gardner and Richard Boles:

Is a "Mitochondrial Psychiatry" in the Future? A Review

The field of "mitochondrial medicine" has advanced rapidly since the first patient with a mitochondrial disorder, a concept primarily used for defects of the respiratory chain, was described in 1962 and the first mitochondrial DNA (mtDNA) mutations were described in 1988. Because of the ubiquitous requirement for energy and unique aspects of mtDNA genetics, mtDNA mutations are known to cause a bewildering spectrum of clinical manifestations. However, because of its high-energy requirement, brain is the primary tissue affected in mitochondrial disorders. Using a variety of approaches, mitochondrial function has been shown in numerous studies to be abnormal in patients with schizophrenia and depression. Although less studied, an increase of psychiatric symptoms and disorders, in particular depression, are likely present in patients with mitochondrial disorders. The major categories of drugs used to treat schizophrenia and depression have been demonstrated to exert effects on mitochondria. The authors conclude that an association between energy metabolism and the mental disorders of schizophrenia and depression has been well documented, but that no conclusive evidence as yet demonstrates a causal relationship. A "mitochondrial psychiatry" model is proposed in which a moderate reduction in mitochondrial energy metabolism, genetically determined and/or acquired, is one predisposing factor in the multi-factorial development of certain chronic mental disorders. Clinical implications of our hypothesis, present and future, include the presence of co-morbid somatic symptoms/conditions, and specific treatment at least in highly-selected cases.

The association studies linking certain mtDNA polymorphisms to mental disorders like schizophrenia or Alzheimer's are potentially confounded by population history, which has spread some initially rare mtDNA variants far from their points of origin and to relatively high frequencies (see exchange between Kato 2001b and McMahon et al. 2001). Two problems make mtDNA-disease linkage difficult. First, mtDNA is nonspecific in its activity -- expressed in all cell types -- so that it is hard to establish clear biochemical pathways leading to particular neurophysiological disorders. Second, there is no possibility of localizing mtDNA variants by LD, since it is entirely linked.

Another issue is that mtDNA coding polymorphisms in humans often vary among other primate species. There is an argument (employed by McMahon et al. 2001) that coding variation found naturally among different primate lineages is unlikely to be functionally relevant in humans -- in other words, such variations are likely to be functionally neutral. But given the extensive behavioral variability of other primates, this argument by itself seems weak -- there is no reason why a variant allele associated with neurophysiological variation in humans should not also vary amont primate lineages. It seems just as likely that such variants may be especially variable among other primates, because they may provide targets for selection on behavior outside of the human context.

Some of these problems and some other work were reviewed by Tadafumi Kato in a 2001 Molecular Psychiatry review:

The other, forgotten genome: mitochondrial DNA and mental disorders

This paper summarizes recent research on mitochondrial DNA (mtDNA) which might be described as the 'other, forgotten genome'. Recent studies suggest the possible pathophysiological significance of mtDNA in schizophrenia and neurodegenerative and mood disorders. Decreased activity of the mitochondrial electron transport chain has been implicated in both Parkinson's and Alzheimer's disease and while age-related accumulation of mtDNA deletions has been suggested as a possible cause, there is no concrete evidence that particular mtDNA polymorphisms are responsible. In schizophrenia, the activity and/or mRNA expression of complex IV are involved, but the direction of the alteration is not the same and there is no evidence linking schizophrenia with mtDNA. In bipolar disorder, there is some evidence of parent-of-origin effects and association with mtDNA polymorphisms but further investigation is needed to elucidate the role of mtDNA in mental disorders.

Later research has employed whole-mtDNA screening to try to resolve such problems. For example, Martorell and colleagues (2006) screened maternal-offspring pairs affected by schizophrenia to find candidate mtDNA polymorphisms that contribute to the disorder:

New variants in the mitochondrial genomes of schizophrenic patients

The impaired mitochondrial function hypothesis in schizophrenia is based on evidence of altered brain metabolism, morphology, biochemistry and gene expression. Mitochondria have their own genome, which is needed to synthesize some of the subunits of the respiratory chain enzymes. Mitochondrial DNA (mtDNA) is maternally inherited and we observed an excess of maternal transmission of schizophrenia in a set of parent-offspring affected pairs. We therefore hypothesized that mutations in the mtDNA may contribute to the complex genetic basis of schizophrenia. The entire mtDNA of six schizophrenic patients with an apparent maternal transmission of the disease was sequenced and compared to the reference sequence. We have identified 50 variants and among these six have not been previously reported. Three of them were missense variants: MTCO2 7750C>A, MTATP6 8857G>A and MTND4 12096T>A. These were maternally inherited because they were also present in the mtDNA of their respective schizophrenic mothers and none of them were found in 95 control individuals. The MTND4 12096T>A (Leu446His) is a heteroplasmic variant present in five of the six mother-offspring patient pairs that triggers a non-conservative substitution in the ND4 subunit of complex I. Sequence alignment of 110 ND4 peptides from all eukaryotic kingdoms shows that only hydrophobic amino acids are found in this position. Moreover, leucine was conserved or substituted by an isoleucine in all mammalian species. This indicates that the presence of histidine could affect complex I activity in patients with schizophrenia.

Well, there's an example of a change not found in other lineages, and putatively under recurrent mutation as a rare disease-associated variant in humans.

Most disease-associated mitochondrial variants presumably do result from recurrent mutations under purifying selection. Different from nuclear genes, the mtDNA has a very high rate of mutations. This means that somatic mosaicism (i.e., different mtDNA mutations accumulating in different parts of the body over time) or heteroplasmy (i.e., different mtDNA sequences within given cells) play a role in some of the disorders of aging and senescence, such as Parkinson's disease.

There is now a substantial literature linking the common mtDNA haplogroups with longevity. For example, De Benedictis et al. (1999) found that Italian centenarians were significantly more likely to carry mtDNA haplogroup J than a set of younger individuals. Interestingly, Rose et al. (2001) found that the haplogroup J mutations were also associated with some complex diseases, concluding:

The general picture that emerges from the study is that the J haplogroup of centenarians is surprisingly similar to that found in complex diseases, as well as in Leber Hereditary Optic Neuropathy. This finding implies that the same mutations could predispose to disease or longevity, probably according to individual-specific genetic backgrounds and stochastic events. This data reveals another paradox of centenarians and confirms the complexity of the longevity trait.

The specificity of genetic background was also suggested by Dato et al. (2004), who found no evidence of an increase of haplogroup J with age cohorts in their southern European sample. Population-specific effects due to allelic background have the potential to confound many kinds of association studies, particularly those related to longevity -- for which frequency changes over time in one or more genes are also a consideration.

All this is a bit of a prologue to a new paper, "An enhanced MITOMAP with a global mtDNA mutational phylogeny", by Eduardo Ruiz-Pesini and colleagues from Doug Wallace's lab:

The MITOMAP (http://www.mitomap.org) data system for the human mitochondrial genome has been greatly enhanced by the addition of a navigable mutational mitochondrial DNA (mtDNA) phylogenetic tree of 3000 mtDNA coding region sequences plus expanded pathogenic mutation tables and a nuclear-mtDNA pseudogene (NUMT) data base. The phylogeny reconstructs the entire mutational history of the human mtDNA, thus defining the mtDNA haplogroups and differentiating ancient from recent mtDNA mutations. Pathogenic mutations are classified by both genotype and phenotype, and the NUMT sequences permits detection of spurious inclusion of pseudogene variants during mutation analysis. These additions position MITOMAP for the implementation of our automated mtDNA sequence analysis system, Mitomaster.

The map characterizes apparent disease-linked mutations, which anyone can cruise to her heart's content. The paper also provides a brief account of the way that different haplogroups got their names, and their geographical distributions.

That paper is part of a special database issue of Nucleic Acids Research, which has short articles on the latest and greatest versions of many publicly accessible databases in molecular biology and genetics. All the papers are free, and it is a tremendous opportunity to learn about the fundamental data of genomics.

References:

Dato S, Passarino G, Rose G, Altomare K, Bellizi D, Mari V, Feraco E, Franceschi C, De Benedictis G. 2004. Association of the mitochondrial DNA haplogroup J with longevity is population specific. Eur J Hum Genet 12:1080-1282. doi:10.1038/sj.ejhg.5201278

De Benedictis G, Rose G, Carrieri G, De Luca M, Falcone E, Passarino G, Bonafé M, Monti D, Baggio G, Bertolini S, Mari D, Mattace R, Franceschi C. 1999. Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans. FASEB Journal 13:1532-1536.

Gardner A, Boles RG. 2005. Is a "Mitochondrial Psychiatry" in the future? A review. Curr Psychiatry Rev 1:255-251. doi:10.2174/157340005774575064

Kato T. 2001a. The other, forgotten genome. mitochondrial DNA and mental disorders. Mol Psychiatry 6:625-633. Abstract

Kato T. 2001b. DNA Polymorphisms and bipolar disorder (letter). Am J Psychiatry 158:1169-1170.

Martorell L, Segués T, Folch G, Valero J, Joven J, Labad A, Vilella E. 2006. New variants in the mitochondrial genomes of schizophrenic patients. Eur J Hum Genet 14:520-528. doi:10.1038/sj.ejhg.5201606

McMahon FJ, Chen Y, Torroni A. 2001. Dr. McMahon and colleagues reply to "DNA Polymorphisms and bipolar disorder." Am J Psychiatry 158:1170.

Rose G, Passarino G, Carrieri G, Altomare K, Greco V, Bertolini S, Bonafè M, Franceschi C, De Benedictis G. 2001. Paradoxes in longevity: sequence analysis of mtDNA haplogroup J in centenarians. Eur J Hum Genet 9:701-707. Abstract

Ruiz-Pesini E, Lott MT, Procaccio V, Poole JC, Brandon MC, Mishmar D, Yi C, Kreuzinger J, Baldi P, Wallace DC. 2007. An enhanced MITOMAP with a global mtDNA mutational phylogeny. Nucleic Acids Res 35:D823-D828. doi:10.1093/nar/gkl927

Nature has a little article this week by Fran Van Heuverswyn et al. announcing that SIV (the primate relative of HIV) has been found in wild populations of Western lowland gorillas.

The finding of distinct but related SIVgor strains in gorillas living nearly 400 km apart suggests that, as in chimpanzees, SIV infection is endemic in gorillas. An alternative explanation could be that gorillas acquire SIV sporadically from chimpanzees, but this seems unlikely as no chimpanzee community surveyed so far, including several from habitats that overlap with those of the SIVgor-positive gorillas, harbour group O-like viruses (see supplementary information). The phylogenetic relationships shown in Fig. 1b argue that chimpanzees were the original reservoir of SIVs now found in chimpanzees, gorillas and humans; that distinct chimpanzee communities in southern Cameroon transmitted divergent SIVcpz to humans, giving rise to HIV-1 groups M and N1; and that chimpanzees transmitted HIV-1 group O-like viruses either to gorillas and humans independently, or to gorillas that then transmitted the virus to humans (Van Heurverswyn et al. 2006:164).

OK, here's what I want to know: If the virus originated in chimpanzees, I can understand that it might have moved to humans by bushmeat consumption. But how did it move to gorillas?

The article suggests it may have crossed from humans to gorillas through hunting, and the gorilla lineages do cluster phylogenetically with some human HIV lineages, so it's not impossible. But it's hard to figure just how this is supposed to work in practice. Well, it's a stumper!

References:

Van Heuverswyn F and 15 others. 2006. Human immunodeficiency viruses: SIV infection in wild gorillas. Nature 444:164. DOI link

I'll be lecturing on hemoglobinopathies again this week, and I stumbled across this 2001 article by Malcolm Gladwell, profiling Fred Soper and the early 20th century effort to eradicate malaria.

This passage is from a longer section describing his work eliminating invasive Anopheles gambiae from Brazil in 1938:

Four thousand men were put at his disposal. He drew maps and divided up his troops. The men wore uniforms, and carried flags to mark where they were working, and they left detailed written records of their actions, to be reviewed later by supervisors. When Soper discovered twelve gambiae in a car leaving an infected area, he set up thirty de-insectization posts along the roads, spraying the interiors of cars and trucks; seven more posts on the rail lines; and defumigation posts at the ports and airports. In Soper's personal notes, now housed at the National Library of Medicine, in Bethesda, there is a cue card, on which is typed a quotation from a veteran of the Rockefeller Foundation's efforts, in the early twentieth century, to eradicate hookworm. "Experience proved that the best way to popularize a movement so foreign to the customs of the people . . . was to prosecute it as though it were the only thing in the universe left undone." It is not hard to imagine the card tacked above Soper's desk in Rio for inspiration: his goal was not merely to cripple the population of gambiae, since that would simply mean that they would return, to kill again. His goal was to eliminate gambiae from every inch of the region of Brazil that they had colonized--an area covering some eighteen thousand square miles. It was an impossible task. Soper did it in twenty-two months.

There were the great successes, and some hubris, and something of a tragic end. But it's a timely story, considering that WHO has stepped up its recommendations to use DDT to fight malaria in Africa. (via Instapundit)

And Soper was a Kansas boy.

Thanks to an enterprising student, I have an AP story about the discovery of a risk allele for prostate cancer that has different frequencies in different groups.

Scientists have identified a common genetic marker that signals a 60 percent heightened risk of prostate cancer in men who carry it, and it may help explain why black men are unusually prone to the disease, a new study says.

The DNA variant may play a role in about 8 percent of prostate cancers in men of European extraction and 16 percent of the cancers in blacks, researchers said.

So, what does somebody like me do with this information? I'm interested in cases where populations are different as illustrations of human biological variation and its evolutionary causes. Here, we have medical data and genomic information that appears to show a geographic difference among men in their risk. But we have to look at the study to see what that means. Here's the abstract:

With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10^-11). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of ˜ 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.

This is actually a great case study in the complexity of finding the genetic causes of disease:

As only the microsatellite allele showed significant association in the African American case-control group, and it is contained in a smaller LD block in African Americans than in populations of European ancestry (Supplementary Fig. 2 online), we propose that the region most likely to contain the functional variant can be narrowed down to positions 128.414-128.474 Mb (NCBI build 34). This region contains one spliced EST (AW183883) and three single-exon ESTs (BE144297, CV364590 and AF119310) in addition to a few predicted genes, but no known genes. No microRNAs have been detected within the block. Expression analysis in various cDNA libraries confirmed only the expression of the AW183883 EST (Supplementary Methods). We identified four different splice variants of AW183883 by 5'and 3' RACE that were verified by RT-PCR and RNA blot analysis (Fig. 2a). Using the AW183883 EST as a probe on an RNA blot, we detected a 1.5-kb signal only in testis, consistent with the size of the two longer forms. The two shorter transcripts harboring exons 6-8 were detected only in normal (0.6-kb transcript) and malignant (0.6- and 0.9-kb transcripts) prostate cell lines, not in the other tissues analyzed (Fig. 2b,c). The predicted ORFs for these transcripts did not show significant homology to known proteins.

In other words, although they have narrowed down a region around this marker as a risk factor for prostate cancer, they don't know what specific genetic change causes the risk. It isn't any of the SNPs in the HapMap set. They can tell from the HapMap variation that the linkage block is narrower in Africans, so that the causative variant must be fairly near it. There are no characterized genes and no known microRNAs in the region, but there are some possible genes that haven't been characterized. "cDNA" libraries are complements of mRNA expressed within cell lines, only one of these may correspond to the region in question, and one variant is expressed in testis and prostate cell lines. They don't know what it is or what it does.

All of that analysis is bioinformatics -- taking databases of known gene expression in cell lines, genetic variation among people, and identified genes, SNPs and microsatellite markers and integrating them into a picture of associations. What is left is a lot of biology -- what does the key genetic variant change; what gene is it part of; what is the normal role of the gene within prostate (or elsewhere); why does it become pathological; etc. And most important, how can we fix it?

My interest is at the opposite end --- why did this allele become common; why does it have different frequencies in different groups; how old is it?

There are no answers to these questions -- there rarely are in studies like this. But put several of them together and we may start to uncover much about human prehistory and the conditions of life in ancient populuations. Does this risk allele correspond to different ancient environments? Different population dynamics? Or is it just different by chance?

That is the breakdown on the one hand between bioinformatics and biology, and on the other between functional biology and evolutionary biology.

References:

Amundadottir LT and 45 others. 2006. A common variant associated with prostate cancer in European and African populations. Nature Genet (online early) DOI link