IMED1002 - Chromosome Changes: Number (L28)

How many alleles do we have

2, one from each parent

Numerical chromosomal abnormalities involve

- gain or loss of chromosomes

- Number of chr in a basic set: monoploid number (X). e.g bees, ants, wasps etc, hence they are sterile (except queen bee)

- organisms with multiples of basic chr set = euploids

- normal human cells are either: haploid (one set, n) or diploid (2 sets, 2n)

- these are both normal euploidy

Chromosome Changes

- normal means a human who has all the genes in the correct place

- the sequence shown represents a chromosome

Types of Chromosome Variants (NAMING ONLY)

- three basic categories: aberrant euploidy (polyploidy), aneuploidy, chromosome rearrangements (alter structure, not in these slides)

Aberrant Euploid

one or more complete sets of chromosomes are added/lost

- if you lose a set, you have 23 chr

- if you gain a set, you have 69 chr

- NOT VIABLE for life

Aneuploid

number of chromosomes is altered (one or more individual chr added or deleted)

Euploids

- Monoploid: an individual of a "normally" diploid species with one copy of the basic chromosome set = n (not viable in humans)

- Euploid: has multiples of basic chromosome set (e.g Diploid is 2n (normal human), Triploid is 3n (aberrant euploidy)

- Polyploid: More then 2 sets

Aneuploid Designation

- number of chromosomes is altered (one or more individual chr added or deleted)

- Monosomic: 2n-1

- Trisomic: 2n+1

- Nullisomic: 2n-2

- Sex Chromosome Changes: XXY, XYY, XXX or X0 (0=null)

SUMMARY SO FAR

Aneuploidy: change in number of individual chr. Types of Aneuploidy: (n refers to haploid number), the designations are important:

- Nullisomy: loss of both members of homologous set of chr (2n-2) (NOT VIABLE)

- Monosomy: loss of a single chr (2n-1)

- Trisomy: gain of a single chr (2n+1)

- Tetrasomy: gain of 2 homologous chromosomes (2n+2)

Meiosis and Aneuploid (Nondisjunction at Meiosis 1)

- Aneuploid cells can arise through nondisjunction

- Paired chromosomes fail to separate during meiosis and migrate to same daughter cell

- can occur at 1st meiotic division or second meiotic division

- usually if nondisjunction occurs at meiosis 1 none of these zygotes are going to be viable

Meiosis and Aneuploid (Nondisjunction at Meiosis 2)

- Human autosomal monosomics not viable, due in in utero

- some human autosomal trisomics are viable

Autosomal Trisomy (2n+1)

- for final exam have to be able to look at a karyogram and tell if its normal or abnormal, if its XX or XY (without numbers beneath them)

- have an extra copy of one autosome

- in diploid organisms, autosomal trisomy generally results in abnormality or death

- however, can have viable trisomics and even fertile trisomics. e.g trisomy 21

Autosomal Trisomy in Humans

Trisomy 21: Down Syndrome, around 0.15% of live births

- People are viable and active.

- Most Down's patients have extra chromosome 21, sporadic and have no family history of aneuploidy

- Other human trisomy to survive birth: 8, 9, 13, 18 and 22

- severe developmental abnormalities. Other autosomal trisomics due in utero

Trisomy 21 Phenotype

- Incidence related to maternal age, cause still not verified. Less pronounced link to paternal age

Why does risk of having a child with trisomy increase as you get older

- in euploids, ratio of any one gene to any other is 1:1

- in Aneuploids, ratio differs by 50% from wild type. 50% for monosomics and 150% for trisomics

- This makes the aneuploid genes out of balance

- Generally, the amount of transcript a gene makes is around the number of copes of that gene in a cell

- so the more copies of the gene, the more transcripts and the more protein translated

- called the gene-dosage effect

- e.g if you have two copies of the gene you're gonna have two copies of the transcript. If you have 3 copies of the gene, you're gonna have 3 copies of the transcript

- more copies = more transcripts = more proteins

- to be a viable human, you have to have gene products and proteins in relative balance to one another

Gene Balance

- Normal physiology relies on euploid gene balance, if this is not maintained, may get imbalance in cellular pathways: this is particularly important during development

- the entire aneuploid phenotype is really a combination of all the imbalances of the genes on the chromosome that is missing or present as an extra copy

- Genome imbalance: ratio of genes altered, ratio of gene products altered, change in phenotype, expression of deleterious recessive alleles

Phenotype Changes and Gene Balance

- Phenotype changes may result from only a few "vital" or "major" genes on the chromosome, not necessarily all genes on it

Such genes are said to be:

- haplo-abnormal (if only one gene copy gives an abnormal phenotype) or

- triplo-abnormal (if 3 copies of the gene give an abnormal phenotype) (e.g trisomy 21)

- such genes are known to significantly contribute to the aneuploid phenotype (next lecture)

Unbalanced Gene Dosage

- due to imbalance in amounts of gene products

- Amount of protein synthesised often directly related to number of gene copies

- Proper development needs interaction of proteins at correct dosage (thats the reason so many trisomics and monosomics die in utero)

- Sometimes duplications are evolutionarily beneficial. e.g human globin genes

Gene Balance and Sex Chromosomes

- Y chromosome is a degenerate X, with very few functional genes, other then sex determination and/or sperm production

- X chromosome contains vital "housekeeping" genes

- Yet the X chromosome's housekeeping genes are expressed almost equally in males and females, even though females have double the number of these genes: known as dosage compensation

- X chromosome is vital for life

Even though females have double the X chromosoms as males

they only express 1 of these chromosomes in their cells (X chromosome inactivation)

Transcriptionally Active Chromosomes

- in humans, only one X chromosome is transcriptionally active in any somatic cell

- So, both XX and XY individuals have equivalent transcription from their X chromosome genes

- Females are mosaics and have some other cells express genes from the maternal X and other cells from the paternal X

- Such X chromosome "inactivation" also explains why XXX individuals are normal, they transcribe from only one X chromosome in any one cell

X Chromosome Monosomic (2n-1)

- Some X-chr monosomics are viable

- Turner syndrome (X0) 45 chr: 44 autosomes, only 1 X chr. around 1 in 5000 female births (infertile individuals)

Human Sex Chromosome Trisomy

- XXX, phenotypically normal, fertile females. Meiosis gives pairing of only two of the X's. The third X does not pair and is not transmitted. Hence gametes are X only. (The extra X is silenced). Meiosis will give pairing of two of the X chromosomes, and the third one is lost, hence not passed on

- XYY, mostly fertile, no "true" predisposition to violence. Meiosis gives normal pairing of X with one of the Y's. The other Y does not pair and is not transmitted to gametes. The resultant gametes therefore have either X or Y, as any normal gamete does.

- So, for both of these trisomies, the defect is not passed onto the next generation

Aneuploid XXY Male

- aneuploids for X and Y chromosome occur at around 1/1000 live births

- XXY male = Klinefelter syndrome: infertile, slightly lower IQ, lanky build