Charles He, Jessica McClendon, Kaelin Priger , and Wangshu Yang Group B2

1. Genes and Mutations Charles He, Jessica McClendon, KaelinPriger, and Wangshu Yang Group B2

2. A mutant is an individual that carries a mutation, particularly a new or rare mutation. A mutation is any change in the hereditary material of an organism.1 Are You A Mutant? 1 Freeman, 241.

3. Mutations can occur as… • Silent mutations • Missense (replacement) mutations • Nonsense mutations • Frameshift mutations Image courtesy of Creative Commons

4. LoF variants in human genes Loss of function (LoF) variants are genetic variants predicted to severely disrupt protein-coding genes. Genome-sequencing studies indicate that humans carry many genetic variants predicted to cause LoF. LoF variants may be deleterious, beneficial, or neutral to humans. MacArthur, et al, 2012.

5. Obtaining and filtering candidate LoF variants Data collected from individuals represent three population groups: African Nigeria (YRI), European Utah (CEU), and Chinese and Japanese jointly (CHB+JPT). Identify likely sequencing and filter out high confidence human variants predicted to disrupt protein-coding genes. Study: “A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes” by Daniel G. MacArthur, et al, Science, 2012, Volume 335.

6. Study by MacArthur’s group looked at 185 human genomes. • Found that on average, humans have around 100 LoFvariants on protein-coding genes. • Around 20 genes completely inactivated. • Specifically, European human genome had 97 LoF variants and 18 were in homozygous state. • Those with African ancestry have 25% higher high-confidence LoF variants than those with non-African ancestry. Do you have mutations? MacArthur, et al, 2012.

7. Commentary by Quintana-Murci relates MacArthur’s findings to 3 hypotheses about genetic variations. • “Less is more” hypothesis – If they LoF variants are advantageous, they may increase in frequency because of positive natural selection. • “Less is nothing” hypothesis – If the LoF variants are tolerated and don’t have an impact on survival, they drift neutrally through the population. • “Less is less” hypothesis – If the LoF variants are deleterious, they will become less frequent through natural selection. Quintana-Murci, 2012.

8. Strong Negative Natural Selection is projected to oppose inactivating protein coding genes forcing the true variation levels to decrease Purifying selection is projected to stop deleterious alleles from forming high populations, which explains the rarity of complex disease risk in LoFgenes Natural Selection MacArthur, et al, 2012. Quintana-Murci, 2012.

9. Some LoF Tolerant Genes may have no affect and be inactive. • Homozygously inactivated genes are an example. LoF Tolerant genes are “less conserved, and have fewer protein-protein interactions.” They also improve chemosensation (related to smell). Using LoF Tolerant Genes MacArthur, et al, 2012.

10. 26 known recessive disease-causing mutations in LoF variants. Diseases include Crohn’s disease, Leber congenital amaurosis, harlequin ichthyosis, osteogenesisimperfecta, Tay-Sachs disease, Charcot-Marie-Tooth disease, mucolipidosis, etc • Supports the “less is less” hypothesis Effects of LoF variants on diseases MacArthur, et al, 2012. Quintana-Murci, 2012.

11. LoF variants can affect the genes PKD1L3 and PKD2L1. These two genes produce proteins that are accumulated at the taste buds of the mouth, and are responsible for the sour-taste receptors. Ishimaru, 2006. Effect of LoF variant on phenotypes

12. Everyone is a mutant!

13. ReferencesFreeman, Scott. Biological Science. Vol. 1-3. San Fransicso, CA: Benjamin Cummings, 2011.Y. Ishimaru., et al. Transient receptor potential family members PKD1L3 and PKD2L1 form a candidate sour taste receptor. Proc. Natl. Acad. Sci. U.S.A. 103,  (2006).MacArthur, D.G., et al. 2012. A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes. Science 335(Feb): 823-828. Quintana-Murci, L. 2012. Gene Losses in the Human Genome. Science 335(Feb): 806-807.Images courtesy of Creative Commons