Genetic Basis of Human Diseases

Disorders related to mutations in single genes with large effects

- Cause the disease or predispose to the disease

- Highly penetrant

- Caused by single gene mutations and usually follow the classic Mendelian pattern of inheritance

Chromosomal Disorders

- Arise from structural or numerical alteration in the autosomes and sex chromosomes

- Uncommon but associated with high penetrance

Complex Multigenic Disorders

Caused by interactions between multiple variant forms of genes and environmental factors

Mutations

Point mutations within coding sequences

-Silent mutations

-Missense mutations

-Nonsense mutations

Mutations within noncoding sequences

Deletions and Insertions

- Frameshift mutations

Trinucleotide-repeat mutations

Point mutations in coding sequences

or substitution is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a sequence

Silent mutations

Mutations in DNA that do not have an observable effect on the organism's phenotype. They are a specific type of neutral mutation

Missense mutations

Mutations that alter the meaning of the sequence of the encoded protein

Two types of missense mutations

Conservative and nonconservative missense mutations

conservative missense mutation

Substituted amino acid is biochemically similar to the original

Causes little change in function

Nonconservative missense mutations

Replaces the normal amino acid with a biochemically different one

Nonsense mutation

A point mutation may change amino acid codon to a chain terminator or stop codon when cell signals to stop protein production and results in a shortened and malfunctioned protein

Mutations within noncoding sequences

Interfere with binding of transcription factors and leads to marked reduction or lack of transcription

Deletion mutation

involves the loss of one or more nucleotides (in multiple of threes of not) from a segment of DNA

Insertion mutation

Permanent change in DNA sequence caused by the addition of nucleotides (in multiple of three or not)

Non-frameshift mutation

Small deletions or insertions of base pairs involved is three or multiple of three

The reading frame will remain intact and an abnormal protein lacking or gaining one or more amino acids will be synthesized

Frameshift mutation

The number of affected coding bases is not a multiple of threes

This results in an altered reading frame if the DNA strand

Typically results in incorporation of a variable number of incorrect amino acids followed by a premature stop codon

Trinucleotide-repeat mutations

Characterized by amplification of a sequence of three nucleotides

Euploid

any exact multiple of the haploid number of chromosomes (23). 46,XX for the female. 46XY for male.

Abnormalities in chromosome numbers

Polyploidy

-Triploidy

Aneuploidy

-Monosomy

-Trisomy

Polyploidy

Euploid cells with more than the normal diploid number of 46 (2n) chromosomes: 3n, 4n

Triploidy

Those with 3 haploid sets of chromosomes (3n)

Aneuploidy

An error occurs in meiosis or mitosis and a cell acquires a chromosome complement that is not the exact multiple of 23

-Cells do not contain a multiple of haploid number of chromosomes

Monosomy

Occur when only 1, instead of the normal 2, of a given chromosome is present

Turner Syndrome 45, X

Results from complete or partial monosomy of the X chromosome

Trisomy

Characterized by the presence of 3 chromosomes, instead of the normal 2, of any particular chromosome

- Most common form of aneuploidy

Trisomy - nondisjunction

The failure of chromosomes to disjoin normally during meiosis

Klinefelter syndrome

Male hypogonadism that occurs when there are two or more X chromosomes and one or more Y chromosomes

Deletions

Loss of a portion of a chromosome

Most are interstitial but rarely terminal deletions may occur

Ring chromosome

Formation of a ring chromosome by a break in each arm, loss of the terminal segments and union of the centric segment

Duplication

The presence of extra genetic material from the same chromosome

Can also be sporadic or result from abnormal segregation in translocation or inversion carriers

Inversions

A rearrangement that involves two breaks within a single chromosome with reincorporation of the inverted, intervening segment

Two types of Inversions

Pericentric and paracentric inversions

Pericentric inversions

breaks are in the 2 opposite arms of the chromosome and include the centromere

usually discovered because they change the position of the centromere

Paracentric inversions

• Inversion involving only in 1 arm

Insertion

Occur when a piece of a chromosome broken at 2 points is incorporated into a break in another part of a chromosome

Isochromosome

Consist of 2 copies of the same chromosome arm joined through a single centromere and forming mirror images of one another

Translocation

Involve the transfer of material from one chromosome to another

Two types of translocation

Reciprocal translocation and robertsonian translocation

Balance reciprocal translocation

Result of breaks in nonhomologous chromosomes with reciprocal exchange of the broken segments

Robertsonian Translocation or Centric Fusion

Translocation between two acrocentric chromosomes

Typically the breaks occur close to the centromeres of each chromosome.

Transfer of the segments then leads to one very large chromosome and one tiny one.

Insertion

Occur when a piece of a chromosome broken at 2 points is incorporated into a break in another part of a chromosome