Comparisons between human and chimpanzee genomes indicate that a gene that may function as a wild-type or normal gene in one primate may function as a disease-causing gene in another [The Chimpanzee Sequencing and Analysis Consortium (2005). Nature 437:69–87]. For instance, the PPARG locus (regulator of adipocyte differentiation) is a wild-type allele in chimps but is clearly associated with Type 2 diabetes in humans. What factors might cause this apparent contradiction? Would you consider such apparent contradictions to be rare or common? What impact might such findings have on the use of comparative genomics to identify and design therapies for disease-causing genes in humans?

Verified step by step guidance

1. Step 1: Understand the concept of gene function variability across species. Recognize that a gene's effect can differ depending on the genetic background, environmental context, and evolutionary history of the organism. This means a gene that is 'wild-type' or normal in one species might have a different impact in another species due to these factors.
2. Step 2: Identify factors that could cause a gene to be disease-causing in humans but not in chimpanzees. These include differences in gene regulation, interactions with other genes (epistasis), variations in protein structure or expression levels, and species-specific environmental pressures that influence gene function.
3. Step 3: Consider the frequency of such contradictions. Reflect on evolutionary divergence and the complexity of genomes, which suggest that such differences are not rare but rather relatively common, especially between species that have evolved separately for millions of years.
4. Step 4: Analyze the implications for comparative genomics. Understand that while comparative genomics is a powerful tool for identifying candidate disease genes, these findings highlight the importance of validating gene function in the specific human context before designing therapies, as gene effects may not be directly transferable from model organisms or closely related species.
5. Step 5: Summarize the impact on therapeutic design. Emphasize that these findings encourage a cautious and integrative approach, combining comparative genomics with functional studies in human cells or tissues to ensure that therapies target the correct gene functions and pathways relevant to human disease.

Key Concepts

Gene Function and Allelic Variation

Genes can have different alleles, or versions, that may function differently across species. An allele considered 'wild-type' in one species might cause disease in another due to differences in genetic background, regulatory elements, or protein interactions. Understanding allelic variation helps explain why the same gene can have distinct effects in humans and chimpanzees.

Comparative Genomics and Evolutionary Context

Comparative genomics studies similarities and differences in genomes across species to infer gene function and evolutionary changes. Differences in gene function between species often arise from evolutionary divergence, including changes in gene regulation, environment, or interacting pathways. This context is crucial for interpreting why a gene may be benign in one species but pathogenic in another.

Implications for Disease Research and Therapeutics

Findings that gene functions differ between species highlight challenges in using animal models and comparative genomics for human disease research. Such contradictions suggest caution when extrapolating data across species and emphasize the need for human-specific studies in drug design and therapy development to ensure effectiveness and safety.