GENOME COMPOSITIO

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G R O U P B 1G R E G B E N Z L E O E S P I N O S AD A V I D C A R OR U P E R T W U

LOSS-OF-FUNCTIO

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VARIANTS

INTRODUCTION

Loss-of-Function variants

The genetic variants predicted to severely disrupt protein- coding genes

LoF’s include Single-nucleotide variants (SNVs) and insertion/deletion (indel) variants

Recent studies indicates that LoF variants are not always deleterious

Can exist in healthy individual.

Classify the Lof variants:SNVs and indel

Filter the candidate LoF variants into high-confidence , missense and synonymous.

Analyze the numbers and the properties of LoF variants in the individual genome

Filter the candidate LoF variants into high-confidence LoF, missense and synonymous.

Investigate how LoF variants affect human phenotype and disease risk

Some implications of this research:

Predict the probability of disease causation for novel variants.

High confidence LoF:

Mainly include nonsense and frame-shift variants

Usually deleterious.

Missense LoF:

Can not determined.

OVERVIEW OF STUDY

What would we find if our genome was sequenced?

-LoF Variants-Helpful, Harmful, or Harmless?

-Do these variants affect phenotype?

HOW IS THE EFFECT OF GENETIC VARIANCE ON PHENOTYPE SHOWN?

(Quintana-Murci et al. 2012)

DATA (FIGURE 1)

(MacArthur et al. 2012)

DATA (FIGURE 1)

(MacArthur et al. 2012)

DATA (FIGURE 1)

(MacArthur et al. 2012)

DATA (FIGURE 2)

(MacArthur et al. 2012)

DATA (FIGURE 2)

(MacArthur et al. 2012)

DATA (FIGURE 2)

(MacArthur 2012)

DATA (FIGURE 3)

(MacArthur 2012)

DATA (FIGURE 3)

(MacArthur 2012)

DATA (FIGURE 3)

(MacArthur 2012)

DISCUSSION

How does this relate to our Biology class?

Every person has their own unique genomeResult of mutations Different phenotypes3+ billion base pairs in genome

DISCUSSION

Differing base pairs = loss-of-function variantsSingle base change = point mutation

Types of point mutationsSilentMissense Nonsense Frameshift

ACA TGC ATG CCT

Thr Cys Met Pro

Original DNA Sequence

ACG TGC ATG CCT

Thr Cys Met Pro

Silent Mutation

No change in amino acid sequence

ACA TGC ATG CCT

Thr Cys Met Pro

Original DNA Sequence

CCA TGC ATG CCT

Thr Cys Met ProPro

Missense Mutation

Change in one amino acid

ACA TGC ATG CCT

Thr Cys Met Pro

Original DNA Sequence

ACA TGA ATG CCT

Thr Cys Met Pro

Nonsense Mutation

STOPChange from amino acid to stop codon

ACA TGC ATG CCT

Thr Cys Met Pro

Original DNA Sequence

ACA TGC

Thr Ala

Frame Shift

A TC G CC

Thr Cys Met ProChanges in multiple amino acids

Insertion of base C

mRNA

DNA

Transcription

RNA synthesized from DNA template

DISCUSSION

TranslationRNA delivered to ribosomesEach codon aligns with its anticodonAmino acid produced for each codonAmino acids joined by peptide bonds to form a polypeptide (protein)

TAKE-HOME MESSAGE

“Everyone’s Got Problems”

REFERENCESMacarthur, Daniel G. . "A Systematic Survey of Loss-of-Function Variants in

Human Protein-Coding Genes ." Science 335 (2012): 823-828. Print. Quintana-Murci, Lluis. "Gene Losses in the Human Genome." Science 14

Nov. 2012: 806-807. Print.Freeman, Scott, and Healy Hamilton. Biological science. 4th ed. Upper

Saddle River, N.J.: Pearson Prentice Hall, 2011. Print.Segalat, Laurent. "Loss-of-function Genetic Diseases and the Concept of

Pharmaceutical Targets ." Orphanet 225 (2007): Web. 18 Nov. 2012