Chromosome abnormalities 1 + 2

ways to get chromosome mutations

• loss of genetic material (deletion, missing chromosomes

• gain of genetic material (duplication, extra chromosomes)

• relocation of genetic material (translocation, inversion)

categories of chromosome mutations

• chromosome rearrangements

• aneuploid

• polyploid

chromosome rearrangements

chromosome strucuture is altered

aneuploid

number of chromosomes is altered and one or more individual chromosomes are added/deleted

polyploid

one or more complete sets of chromosomes are added

basic types of rearrangments

• duplications

• deletions

• inversions

• translocation

basic mechanisms of rearrangements

• breakage rejoining

• crossing over between repetitive DNA

tandem duplication

duplication is immediately adjacent

displaced duplication

duplication is some distance away

reverse duplication

duplication is inverted

effects of duplication

• duplication on homozygous individuals will have that duplication on both chromosomes

• duplication on heterozygous individuals will have one wild type and one chromosome with duplication

issues with meiosis with duplication

• duplicated chromosomes want to form a tetrad, aligning the same sequences along the strands of DNA

• duplicated sequences will form a chromosomal loop so other sequences align properly

unbalanced gene dosage

• imbalances in the amounts of gene product

• amount of protein synthesised is directly related to the number of gene copies

• change in relative amounts of gene product can create issues with development

how does gene dosage create issues?

Duplications and mutations that create extra copies of gene can result in extra expression of those gene products. The disproportionate interaction of gene products results in abnormal development.

Haemoglobin

• tetramer of two types of subunits, alpha and beta

• globin genes underwent genetic mutation over cycles of evolution

• different globin genes expressed in different times during development

• arose through duplication

types of globin and time of expression

• epsilon globin expressed in embryo

• gamma globin expressed in embryo and foetus

• delta and beta globin expressed in adult

chromosome deletion

the loss of a chrosome segment and heterozygous individuals for deletion have the normal chromosome loop out during meiosis pairing in prophase 1

efects of deletions

• deletion of centromere means that chromosomes won’t segregate and will be lost

• homozygous deletions where same sequences are removed on both homologs are lethal

• heterozygote deletion has multiple defects

heterzygote defects

• gene imbalance

• pseudodominance where a normally recessive mutation is expressed where the wild type allele is deleted

• haploidinsuffiency as some genes that require two copies for normal function

Cri du chat cause

heterozygous deletion of tip of the short arm of chromosome 5 (5p)

Cri du cat symptoms

• cat like cries in infants

• microencephaly, moonlike face and intellectually disabled

• low fatality rates and many live to adulthood

chromosome inversion

• Chromosome segment is inverted and the chromosome must break in two places.

• a segment of the chromosome is turned 180 degrees

Paracentric inversion

inversions that do not include the centromere

pericentric inversion

inversions that include the centromere

effects of chromosome inversion

• it may break a gene into two parts and it is unlikely to have a functional gene product

• inversion in between genes leads to ivnerted gene order and the disruption of position-dependent regulation leads to mis-expression

paracentric inversion loops

• in a heterozygote, one chromosome has one normal chromosome and one chromosome with an inverted segment

• in prophase 1, chromosomes form an inversion loop to allow homologous sequences to align

crossing over with paracentric inversion

chromosome translocation

movement of genetic material between non-homologous chromosomes or between the same chromosome

nonreciprocal translocation

genetic material moves from one chromosome to another without reciprocal exchange

reciprocal translocation

two way exchange of segments between chromosomes (more common)

effect of translocation

• genes that were formally on different chromosomes are physically linked and affect gene expression

• chromosome break can occur between genes and disrupt gene function

• deletions frequently accomany translocations

when can translocation occur

• can occur in meiosis and abnormalities in all cells of offspring

• in mitosis of somatic cells and abnormalities in affected cell line

Philadephia chromosome

• translocation between chromosome 9 and 22

• cause fusion of bcr1 and abl

• br1-abl fusion protein gives permanent protein kinase activity

abl gene

protein kinase that participates in signal transduction pathway

follicular lymphoma

• translocation between chromosome 14 and 18

• chrom 14 has transcriptional enhancer for B cell specific gene

• when fused with bcl-2 (chr 18), bcl-2 protein is misexpressed giving rise to B cellt tumours

• large amounts of bcl-2 expressed in B cells blocks apoptosis

• unusually long life leads to mutation ccumulation that promotes cell proliferation

euploids

organisms with exact multiples of basic chromosome set

trisomy (aneuploid example)

• 2n + 1 = 24

• gain of a single chromosome

autotriploid (polyploid example)

• 3n = 69, sometimes 69, XXX)

• usually occurs due to polyspermy or maternal derivation from egg having extra set

• does not run in families and not associated with maternal age

• occurs in certain cells:

tetraploidy and its designation

• 4n = 92

• most common probable origin is chromosomal duplication in somatic cell in early-cleavage stage embryo

• usually first trimester miscarriage

nullisomy and its designation

• 2n - 2 = 44

• loss of both memebrs of homologous set of chromosomes

monosomy and its designation

• 2n-1 = 45

• loss of a single chromosome

tetrasomy and its designation

• 2n + 2 = 48

• gain of two homologous chromosomes

two cell divisions of meiosis

• meiosis I is reduction division

• meiosis II is equational division

cause of aneuploid cell

• can arise through non-disjunction

• paired chromosomes fail to seperate during meiosis and migrate to the same daughter cell

• can occur at first or second meiotic division

viability of aneuploidy

• human autosomal monosomics are not viable and die in utero

• some autosomic trisomics are viable

Turner Syndrome

• 2n - 1 = 45

• X chromosome monosomy with only one X chromosome

• typically infertile, heart and developmental issues

trisomics

• 2n + 1

• extra copy of one chromosome and results in abnormality or death

• 8, 9, 13, 18, 21 and 22 survive to birth

• some trisomies can be viable and even fertile (including sex chromosomes)

trisomies in human

aneuploids for x and y occur at 1/1000 live births

klinefelter syndrome

• XXY male

• infertile, lanky build, slightly lower IQ

XYY

• mostly fertile, no ‘true’ predisposition to violence

• meiosis gives normal pairing of XY

• resultant gametes have either X or Y

• defect not passed on

XXX

• phenotypically normal, fertile females

• meiosis gives pairing of only two of the X’s

• defect not passed on

trisomy 21

• extrasome chromosome 21

• 0.15% of all live births, individuals are active and viable

• sporadic and no family history of aneuploidy

• rafer forms of down’s result from translocation event and may be transmitted

incidence of trisomy 21

• incidence related to maternal age

robertsonian translocation

• forms a large one metacentric chromosome from two long arms of acrocentric chromosomes

• the smaller chromosome formed is lost

• reduces chromosome number

down syndrome and translocation

• individuals with robertsonian translocations are carriers and can have children with trisomy 21

• 2/3 of live births will be health and normal (may be carriers)

• 1/3 have down syndrome

• other combinations are aborted

gene balance

• euploids - 1:1 of any one gene to another

• normal physiolocy relies on euploid gene balanced

gene dosage effect

• the amount of transcript a gene makes is related to number of copies of that gene in a cell

• the more copies of the gene, the more transcripts and the more protein translated

aneuploid phenotype

combination of all imbalances of the genes on the chromosome which is missing or present as an extra copy

genome imblance

• ratio of genes altered

• ratio of genes altered

• change in phenotype

• expression of deleterious recessive alleles (monosomy)

Gene balances and sex chromosomes

• Y chromosome have very few functional genes

• X chromosomes contain vital ‘housekeepin genes’

• in mammals only one X chromosome is transcriptionally active in any somatic cell

dosage compensation

• X chromosome housekeeping genes expressed almost equally in males and females

• one X is randomly inactivated forming a Barr body

• females are mosaics for X

barr bodies

• triple X females and Klinefelter males will neautralias extra Xs by forming additional Barr bodies

• X inactivation can help mitigate the effect of chromosome aneuploidies