Animal Rights

Small Changes

| by Dr Ray Greek

An article by Bakircioglu et al. (Bakircioglu et al. 2011) reveals that the size and shape of the human cerebral cortex (the outer most layer of the brain) appears to be due to changes in one gene. Scientists arrived at this conclusion after studying three families that have children with very small brains—microcephaly. The children’s brains were about 10% of normal size. Mutations in the gene NDE1 appear to be responsible. This could mean that the difference between the human cerebral cortex and the cerebral cortex of nonhuman animals is due to this one gene. As I (and others) have stated many times, it does not take huge changes to result in dramatic differences between two otherwise identical genomes. This explains in part why animal models cannot predict human response to drugs and disease. It also explains why using animal models is so seductive; it just makes sense that organisms so similar should mimic each other.

Changes in gene expression are another example of small changes leading to dramatic differences. Scientists are learning how this happens. Pai et al 2011:

The modification of DNA by methylation is an important epigenetic mechanism that affects the spatial and temporal regulation of gene expression. Methylation patterns have been described in many contexts within and across a range of species. However, the extent to which changes in methylation might underlie inter-species differences in gene regulation, in particular between humans and other primates, has not yet been studied. To this end, we studied DNA methylation patterns in livers, hearts, and kidneys from multiple humans and chimpanzees, using tissue samples for which genome-wide gene expression data were also available. Using the multi-species gene expression and methylation data for 7,723 genes, we were able to study the role of promoter DNA methylation in the evolution of gene regulation across tissues and species. We found that inter-tissue methylation patterns are often conserved between humans and chimpanzees. However, we also found a large number of gene expression differences between species that might be explained, at least in part, by corresponding differences in methylation levels. In particular, we estimate that, in the tissues we studied, inter-species differences in promoter methylation might underlie as much as 12%–18% of differences in gene expression levels between humans and chimpanzees. (Pai et al. 2011)

Small differences in genomes have implications for treating disease. In an article in Nature titled, Fifty genome sequences reveal breast cancer's complexity, Meredith Wadman stated:

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Scientists led by Matthew Ellis at Washington University in St. Louis, Missouri, have sequenced the whole genomes of 50 patients' breast cancer tumours alongside matching DNA from the same patients' healthy cells in order to identify genomic alterations present only in the cancerous cells. Their findings, presented today at the Annual Meeting of the American Association for Cancer Research in Orlando, Florida, reveal that these cancers' genetic fingerprints are highly diverse; of the 1,700 gene mutations they found in total, most were unique to individual patients' tumours, and only three occurred in 10% or more. The genomic changes were also of all kinds, from single-nucleotide variations and frame shifts to translocations and deletions . . . Ellis says that the complexity of their results indicates that when it comes to developing therapeutics "very clearly the only way forward is the genome-first approach. No single blockbuster drug will answer the problem of endocrine-therapy resistance".

Animals and human have many things in common. Individual humans have things in common with other individuals and monozygotic twins have even more in common with each other. But the very small differences can outweigh all the commonalities when it comes to disease and drug response.

References

Bakircioglu, M., O. P. Carvalho, M. Khurshid, J. J. Cox, B. Tuysuz, T. Barak, S. Yilmaz, O. Caglayan, A. Dincer, A. K. Nicholas, O. Quarrell, K. Springell, G. Karbani, S. Malik, C. Gannon, E. Sheridan, M. Crosier, S. N. Lisgo, S. Lindsay, K. Bilguvar, F. Gergely, M. Gunel, and C. G. Woods. 2011. The Essential Role of Centrosomal NDE1 in Human Cerebral Cortex Neurogenesis. American journal of human genetics.

Pai, Athma A., Jordana T. Bell, John C. Marioni, Jonathan K. Pritchard, and Yoav Gilad. 2011. A Genome-Wide Study of DNA Methylation Patterns and Gene Expression Levels in Multiple Human and Chimpanzee Tissues. PLoS Genet 7 (2):e1001316.