Structure, Function and Variation in Human Genome

Precision medicine

Medical approach that tailors prevention, diagnosis and treatment to an individual's genetic and biological characteristics

Traditional medicine

Uses the same treatment approach for most patients with the same disease

Benefit of precision medicine

Improved diagnostic accuracy and better targeted treatments

Artificial intelligence in precision medicine

Enhances analysis and application of precision medicine data

Blockchain technology in precision medicine

Supports secure management and sharing of health data

DNA

Deoxyribonucleic acid that stores genetic information and transmits inherited traits

Components of DNA

Deoxyribose sugar, phosphate group and one nitrogenous base

Nitrogenous bases in DNA

Adenine, thymine, cytosine and guanine

Structure of DNA

Double-stranded double helix

Functions of DNA

Template for replication and transcription of RNA

Gene

Segment of DNA that codes for synthesis of a specific protein

Chromosome

Microscopic thread-like structure carrying hereditary information in the form of genes

Composition of chromosome

DNA attached to a protein core

Autosomes

Chromosomes controlling inheritance of all characteristics except sex-linked traits

Sex chromosomes

Chromosomes responsible for sex-linked traits

Number of human autosome pairs

22 pairs

Number of human sex chromosome pairs

1 pair

Total number of chromosome pairs in humans

23 pairs

Gene (formal definition)

Unit of hereditary information occupying a fixed position (locus) on a chromosome

Locus

Fixed position of a gene on a chromosome

How genes exert effects

By directing synthesis of proteins

Location of genes in eukaryotes

Contained within the cell nucleus

Estimated number of genes in humans

20,000–25,000 genes

Genome

Entire genetic material of an organism

Function of genome

Contains all hereditary instructions for building, maintaining and reproducing an organism

Relationship between genome, chromosome, gene and DNA

Genome contains chromosomes, chromosomes contain genes, genes are made of DNA

Human genomes compared to each other

More than 99% identical between unrelated individuals

Unique genome

Every individual has a unique genome except identical twins

Genomics

Study of the structure, function and inheritance of the entire genome

WHO definition of genomics

Study of genes, their functions and related techniques

Genetics

Study of the functioning and composition of individual genes

Difference between genetics and genomics

Genetics studies single genes whereas genomics studies all genes and their interactions

Pharmacogenetics

Study of how a single gene influences drug response

Pharmacogenomics

Study of how the entire genome influences drug response

Central dogma

DNA is transcribed into RNA which is translated into protein

Replication

Process by which DNA serves as a template for new DNA molecules

Transcription

Process of synthesizing RNA from DNA

Translation

Process of synthesizing proteins from RNA

Protein

Functional product of gene expression that carries out cellular functions

Epigenetics

Study of heritable changes in gene expression without changes in DNA sequence

Key feature of epigenetics

Phenotype changes without genotype changes

Epigenomics

Study of functional elements regulating cellular gene expression across the genome

Genome vs epigenome

Genome is largely the same in somatic cells whereas epigenome differs between cell types

Example of cell-specific epigenome

Leukocytes and adipose tissue have different epigenomes

Gene silencing

Reduction or suppression of gene expression

DNA methylation

Epigenetic mechanism that contributes to gene silencing

Histone modification

Epigenetic mechanism regulating accessibility of DNA for transcription

Non-coding RNA (ncRNA)

RNA molecules that regulate gene expression without encoding proteins

microRNA

Small non-coding RNA involved in gene regulation and silencing

Genetic variation

Differences in DNA sequence among individuals

Importance of genetic variation

Contributes to differences in appearance, disease susceptibility and drug response

Percentage similarity between human genomes

>99% identical

Main causes of genetic variation

Mutation, random mating, random fertilization and recombination

Mutation

Permanent change in DNA sequence

Random mating

Source of genetic variation through different parental combinations

Random fertilization

Source of variation through random union of gametes

Crossing over (recombination)

Exchange of DNA between homologous chromosomes during meiosis

SNP

Single nucleotide polymorphism

Definition of SNP

Variation involving a single nucleotide difference

Most common type of genetic variation

SNP

Percentage of human DNA polymorphisms represented by SNPs

Approximately 90%

Location of SNPs

Can occur anywhere in the genome

Effect of SNPs in exons

May or may not alter amino acid sequence

Effect of SNPs in introns

Can affect gene function and regulation without changing protein sequence

Clinical significance of SNPs

May influence disease risk and drug response

SNPs in regulatory regions

Can directly affect gene expression and function

CYP450 polymorphisms

Genetic variants affecting metabolism of about 25% of medications

Possible effects of genetic polymorphisms on medication response

Normal, enhanced, reduced or absent response

Genes affecting warfarin dosing

CYP2C9, VKORC1 and CYP4F2

INDEL

Insertion or deletion of nucleotides in DNA

Insertion

Addition of nucleotides into DNA sequence

Deletion

Removal of nucleotides from DNA sequence

Effect of INDELs

Alter DNA sequence length and may disrupt protein function

Large insertion example

Hemophilia caused by insertion leading to inactivation of a clotting protein

Short INDELs in genetic regions

Approximately 36% occur in genetic regions

Huntington disease mutation

CAG repeat expansion in HTT gene exceeding 35 repeats

Cystic fibrosis mutation

Deletion of three nucleotides at position 508 in CFTR gene

CNV

Copy number variation

Definition of CNV

Intermediate-scale duplication or deletion of DNA segments ranging from 1,000 nucleotides to several million nucleotides

Types of CNVs

Duplications and deletions

Potential effect of CNVs

Can affect multiple genes simultaneously

Diseases associated with CNVs

Autism, Alzheimer's disease and schizophrenia

Single-gene disorder

Disease caused by mutation in one gene

Examples of single-gene disorders

Alpha-thalassemia, beta-thalassemia, cystic fibrosis, sickle cell anemia and Huntington disease

Multifactorial inheritance

Disease caused by interaction of multiple genes and environmental factors

Examples of multifactorial diseases

Cancer, heart disease, Alzheimer's disease and arthritis

Chromosomal disorder

Disease caused by abnormalities in chromosome number or structure

Examples of chromosomal disorders

Down syndrome, Turner syndrome and Klinefelter syndrome

Mitochondrial inheritance

Inheritance of mutations in mitochondrial DNA

Examples of mitochondrial disorders

Leber hereditary optic atrophy (LHON) and MERRF

Down syndrome

Chromosomal disorder caused by chromosomal abnormality

Turner syndrome

Chromosomal disorder involving sex chromosomes

Klinefelter syndrome

Chromosomal disorder involving sex chromosomes

LHON

Leber hereditary optic atrophy, a mitochondrial genetic disorder

MERRF

Myoclonic epilepsy with ragged red fibers, a mitochondrial genetic disorder

Most important relationship in molecular genetics

DNA → RNA → Protein

Most important relationship in genome organization

Genome → Chromosome → Gene → DNA

Most important source of common genetic variation

SNPs

Most important clinical application of genomics

Precision medicine

Most important difference between pharmacogenetics and pharmacogenomics

Single gene effect versus whole genome effect on drug response