Genetics in medicine
Thompson and Thompson, 7th edition
Chapter 1: Introduction
-ome = ‘all’, complete (from greek) genome, exome
Analysis of human genome incl.:
- Control of gene expression
- Human gene validation
- Interaction between genes-environment
Human Genome Project (2003): sequence of all human DNA available
Allows identification of all human genes
Allows determination of extent of variation in different populations
Ultimately allows delineation of how this variation contributes to health and disease
Fundamental insights into many diseases
Virtually any disease is the result of the combined action of genes and environment, but the
relative role of the genetic component may be large or small.
• Chromosome disorders
Defect due to excess/deficiency of genes contained in whole chromosomes or
chromosome segments
7 per 1000 liveborn infants are affected by these, plus it’s the cause of
nearly half of all spontaneous 1st trimester abortions
• Single-gene defects
Cause of defect is a critical error in the genetic info carried by a single gene (present on
one/both alleles or mitochondrial genome)
Affect 2% of population sometime during an entire life span
• Multifactorial inheritance
Familial inheritance patterns that do not fit the characteristic patterns seen in single-gene
defects
Responsible for majority of diseases (cleft, DM, Alzheimer) ~60%
Chapter 2: The Human Genome and the Chromosomal
Basis of Heredity
DNA=deoxyribonucleic acid
Human genome consists of large amounts of this chemical
Gene = unit of genetic information’
~25 000 genes in human genome
Genes are encoded in the DNA and organized onto chromosomes
Chromosome = rod-shaped organelle in nucleus of each cell, it contains chromatin, consisting of
nucleosomes (=complex of DNA + core histones)
1
,Locus = precise position of a gene on a chromosome
Karyotype = characteristic complement of number and morphology of chromosomes of each
species
Cytogenetics = study of chromosomes, their structure and their inheritance
In 1956 it was first established that normal human chromosome number is 46
Soma=body
Somatic cells are all cells that contribute to one’s body with exception cells that develop into
gametes (germline)
Autosomes = chromosomes that are alike in male and females (=22 pairs)
Sex chromosomes = XX in female and XY in males (=1 pair)
Each somatic cell contains 46 chromosomes, arranged in 23 pairs
Members of a pair are homologous chromosomes: they carry the same genes in the same
sequence, but may have slightly different forms of the same genes (=alleles)
DNA structure
DNA is a polymeric nucleic acid macromolecule, composed of 3 types of units:
1) Five-carbon sugar deoxyribose
2) Nitrogen-containing base (A,T,C,G)*
3) Phosphate group
Together 1,2,3 form a nucleotide
*)
o Purine bases: adenine (A) and guanine (G)
o Pyrimidine bases: thymine (T) and cytosine (C)
Nucleotides polymerize into polynucleotide chains by 5’-3’ phosphodiester bonds
[range from 50 million bp (chr 21) to 250 million bp (chr1)]
1953: James Watson and Francis Crick identified native state of DNA as a double helix (right-
handed), held together by hydrogen bonds between pairs of bases: A-T and C-G
Each chromosome consists of a single, continuous DNA double helix
• Total nuclear genome = 46 DNA molecules, totaling > 6 billion nucleotides
o nuclear vs mitochondrial: see later
chromatin= complex of genomic DNA with several classes of chromosomal proteins (histones
and nonhistone proteins)
Histones play a critical role in proper packaging of chromatin. Four core histones:
H2A
H2 x2 constitute octamer around which DNA double helix segment winds
H3 (around 140 bp, see image)
H4
H1 = 5th histone, binds to DNA in the internucleosomal spacer region, ~60 bp
Nucleosome = complex of DNA + core histones
2
, Histone code = pattern of major and specialized histone types and their modifications
Specifies how DNA is packaged and how accessible it is to regulatory molecules that
determine gene expression or other genome functions
Mitochondrial genome
A small but important subset of genes encoded in the human genome resides in the cytoplasm in
the mitochondria exclusively maternal inheritance
Mitochondrial DNA molecule: 16kb in length, 37 genes
o Products of these genes function in mitochondria, but many nuclear genes also function
in mitochondria
Human genome
3 billion base pairs of DNA (~25 000 genes)
<1.5% encodes proteins
~5% contains regulatory elements that influence or determine patterns of gene
expression during development or in different tissues
~50% more or less repetitive DNA contributing to maintenance of chromosome
structure and important source of variation between individuals
o ~10-15% tandem repeats = satellite DNAs
e.g. α-satellite family located at centromere of each human chromosome (units of
~171 bps): role in centromere function by ensuring proper chromosome
segregation during meiosis and mitosis
o ~10% Alu repeats family (~300 bp units)
o ~20% LINEs/L1 family (~6 kb)
o Many other small families
important through mutations/ recombination events (source of disease)
Cell division
Mitosis = ordinary somatic cell division
1 parent cell 2 daughter cells
Diploid, 2n = 46 chromosomes
3
Thompson and Thompson, 7th edition
Chapter 1: Introduction
-ome = ‘all’, complete (from greek) genome, exome
Analysis of human genome incl.:
- Control of gene expression
- Human gene validation
- Interaction between genes-environment
Human Genome Project (2003): sequence of all human DNA available
Allows identification of all human genes
Allows determination of extent of variation in different populations
Ultimately allows delineation of how this variation contributes to health and disease
Fundamental insights into many diseases
Virtually any disease is the result of the combined action of genes and environment, but the
relative role of the genetic component may be large or small.
• Chromosome disorders
Defect due to excess/deficiency of genes contained in whole chromosomes or
chromosome segments
7 per 1000 liveborn infants are affected by these, plus it’s the cause of
nearly half of all spontaneous 1st trimester abortions
• Single-gene defects
Cause of defect is a critical error in the genetic info carried by a single gene (present on
one/both alleles or mitochondrial genome)
Affect 2% of population sometime during an entire life span
• Multifactorial inheritance
Familial inheritance patterns that do not fit the characteristic patterns seen in single-gene
defects
Responsible for majority of diseases (cleft, DM, Alzheimer) ~60%
Chapter 2: The Human Genome and the Chromosomal
Basis of Heredity
DNA=deoxyribonucleic acid
Human genome consists of large amounts of this chemical
Gene = unit of genetic information’
~25 000 genes in human genome
Genes are encoded in the DNA and organized onto chromosomes
Chromosome = rod-shaped organelle in nucleus of each cell, it contains chromatin, consisting of
nucleosomes (=complex of DNA + core histones)
1
,Locus = precise position of a gene on a chromosome
Karyotype = characteristic complement of number and morphology of chromosomes of each
species
Cytogenetics = study of chromosomes, their structure and their inheritance
In 1956 it was first established that normal human chromosome number is 46
Soma=body
Somatic cells are all cells that contribute to one’s body with exception cells that develop into
gametes (germline)
Autosomes = chromosomes that are alike in male and females (=22 pairs)
Sex chromosomes = XX in female and XY in males (=1 pair)
Each somatic cell contains 46 chromosomes, arranged in 23 pairs
Members of a pair are homologous chromosomes: they carry the same genes in the same
sequence, but may have slightly different forms of the same genes (=alleles)
DNA structure
DNA is a polymeric nucleic acid macromolecule, composed of 3 types of units:
1) Five-carbon sugar deoxyribose
2) Nitrogen-containing base (A,T,C,G)*
3) Phosphate group
Together 1,2,3 form a nucleotide
*)
o Purine bases: adenine (A) and guanine (G)
o Pyrimidine bases: thymine (T) and cytosine (C)
Nucleotides polymerize into polynucleotide chains by 5’-3’ phosphodiester bonds
[range from 50 million bp (chr 21) to 250 million bp (chr1)]
1953: James Watson and Francis Crick identified native state of DNA as a double helix (right-
handed), held together by hydrogen bonds between pairs of bases: A-T and C-G
Each chromosome consists of a single, continuous DNA double helix
• Total nuclear genome = 46 DNA molecules, totaling > 6 billion nucleotides
o nuclear vs mitochondrial: see later
chromatin= complex of genomic DNA with several classes of chromosomal proteins (histones
and nonhistone proteins)
Histones play a critical role in proper packaging of chromatin. Four core histones:
H2A
H2 x2 constitute octamer around which DNA double helix segment winds
H3 (around 140 bp, see image)
H4
H1 = 5th histone, binds to DNA in the internucleosomal spacer region, ~60 bp
Nucleosome = complex of DNA + core histones
2
, Histone code = pattern of major and specialized histone types and their modifications
Specifies how DNA is packaged and how accessible it is to regulatory molecules that
determine gene expression or other genome functions
Mitochondrial genome
A small but important subset of genes encoded in the human genome resides in the cytoplasm in
the mitochondria exclusively maternal inheritance
Mitochondrial DNA molecule: 16kb in length, 37 genes
o Products of these genes function in mitochondria, but many nuclear genes also function
in mitochondria
Human genome
3 billion base pairs of DNA (~25 000 genes)
<1.5% encodes proteins
~5% contains regulatory elements that influence or determine patterns of gene
expression during development or in different tissues
~50% more or less repetitive DNA contributing to maintenance of chromosome
structure and important source of variation between individuals
o ~10-15% tandem repeats = satellite DNAs
e.g. α-satellite family located at centromere of each human chromosome (units of
~171 bps): role in centromere function by ensuring proper chromosome
segregation during meiosis and mitosis
o ~10% Alu repeats family (~300 bp units)
o ~20% LINEs/L1 family (~6 kb)
o Many other small families
important through mutations/ recombination events (source of disease)
Cell division
Mitosis = ordinary somatic cell division
1 parent cell 2 daughter cells
Diploid, 2n = 46 chromosomes
3
