Lecture 2 - Chromosome Abnormalities and Genetic Disorders

What are chromosome abnormalities?

Large scale changes in chromosome structure or number

What are repeat sequences?

Repeated single nucleotides or whole genes

What are single gene mutations?

Point mutations or small scale changes in a gene

What are multifactorial disorders?

Mutations in multiple genes, may be coupled with environmental causes

What is cytogenetics?

A discipline that matches phenotypes with detectable chromosomal abnormalities

What types of chromosomal changes are studied in cytogenetics?

• Changes in chromosome number (e.g. aneuploidy)

• Changes in chromosome structure (e.g. translocations)

What is aneuploidy?

An abnormal number of chromosomes due to gain or loss of one or more chromosomes

What is a chromosomal translocation

A structural rearrangement in which a segment of one chromosome is transferred to another chromosome

What does fidelity of mitosis mean?

The accuracy of chromosome replication and segregation during cell division

Which cell cycle stages are used in cytogenetics?

Metaphase and interphase

Why are metaphase cells used in cytogenetics?

Chromosomes are highly condensed and visible, allowing numerical and structural analysis

What is a karyotype?

A display of metaphase chromosomes from a single cell arranged in homologous pairs and ordered by size

What is a chromosomal aberration?

A mutation large enough to be detected using light microscopy

What techniques detect chromosomal aberrations?

Light microscopy-based techniques such as karyotyping and fluorescence in situ hybridisation (FISH)

What is the International System for Human Genetics Nomenclature (ISHG)?

A standardised system used to describe and name human chromosomes and chromosomal abnormalities

What was the estimated human chromosome number in the 1920s?

48

What was discovered about human chromosome number in the 1950s?

The correct human chromosome number was found to be 46

What major development occurred in the 1960s regarding chromosomes?

A standard system for chromosome classification was introduced, with chromosomes numbered and arranged in descending order of size

What advance in the 1970s improved chromosome identification?

The introduction of chromosome banding techniques

Why were chromosome banding methods important?

They allowed identification of all chromosomes and provided a standardised way to describe chromosomal abnormalities

How is the ISHG system maintained today?

Scientists meet at regular intervals to update the system based on new technologies and techniques

Why is an international nomenclature system important in genetics?

It ensures consistent, accurate communication of chromosomal findings across laboratories and clinicians worldwide

How many chromosome pairs are shown in a human karyotype?

23 pairs in total

How many pairs of autosomes are in a human karyotype?

22 pairs of autosomes

What sex chromosome combinations are seen in a karyotype?

XX and XY

What information can a karyotype reveal?

• Correct chromosome number and structure

• Sex of the individual

• Certain causes of infertility

What cannot be detected by karyotyping?

Small point mutations or the precise molecular nature of gene mutations

Why must cells be in metaphase to produce a karyotype?

Chromosomes are maximally condensed and visible during metaphase

How are cells arrested at metaphase during karyotype preparation?

By treating dividing cells with a mitotic inhibitor such as colchicine, which prevents spindle fibre formation

Why are cells placed in a hypotonic solution?

To cause cells to swell and burst, spreading the chromosomes apart

What is the purpose of the methanol:acetic acid fixative (3:1)?

To preserve cellular and chromosomal structure

Why are cells dropped onto microscope slides?

To spread chromosomes so they can be clearly visualised and arranged into a karyotype

What is involved in karyotyping after chromosome preparation?

Assigning chromosome numbers and organising chromosomes into homologous pairs based on size

How does centromere position help in karyotyping?

It divides the chromosome into two arms, each ending in a telomere (pter and qter), helping identify individual chromosomes

What is meant by chromosome morphology?

The classification of chromosomes based on the position of the centromere and the relative lengths of the chromosome arms

What is an example of a metacentric chromosome?

Chromosome 1

What is an example of a submetacentric chromosome?

Chromosome 9

What is an example of an acrocentric chromosome?

Chromosome 4

What is an acentric chromosome?

A chromosome that has lost its centromere

Why are acentric chromosomes usually unstable?

Because without a centromere they cannot attach to spindle fibres and are often lost during cell division

What special structural features are common in acrocentric chromosomes?

Secondary constrictions on the p-arms that connect stalks and satellites to the centromere

What are chromosome stalks and satellites?

Very small pieces of DNA attached to acrocentric chromosomes via secondary constrictions

What genes are found in the stalk regions of acrocentric chromosomes?

Genes that code for ribosomal RNA (rRNA)

Why are rRNA genes important?

They are required for ribosome production and protein synthesis

How were human chromosomes identified before the 1970s?

By chromosome size and centromere position, which allowed grouping but not unambiguous identification

Why was early chromosome classification limited?

Chromosomes could be grouped but not uniquely identified without banding techniques

What characterises Group A chromosomes?

They are the largest chromosomes

What characterises Group B chromosomes?

They are slightly smaller than Group A and are submetacentric

What characterises Group C chromosomes?

Medium-sized submetacentric chromosomes

What characterises Group D chromosomes?

Medium-sized acrocentric chromosomes with satellites

What characterises Groups E to G chromosomes?

They contain the smallest chromosomes

What technological advance allowed unambiguous identification of each chromosome?

The introduction of chromosome banding techniques

Which chromosomes are in Group A?

Chromosomes 1–3

Which chromosomes are in Group B?

Chromosomes 4–5

Which chromosomes are in Group C?

Chromosomes 6–12

Which chromosomes are in Group D?

Chromosomes 13–15

Which chromosomes are in Group E?

Chromosomes 16–18

Which chromosomes are in Group F?

Chromosomes 19–20

Which chromosomes are in Group G?

Chromosomes 21–22

What is chromosome banding?

A technique used to stain chromosomes to produce characteristic patterns that allow chromosome identification

What staining method is used in classic karyotyping?

Giemsa staining, producing G-banding patterns

What determines the G-banding pattern of a chromosome?

The specific protein–DNA content along the chromosome

Why are G-banding patterns useful?

Each chromosome has a distinct and consistent banding pattern that allows reliable identification

What is heterochromatin?

Chromatin that is gene-poor and stains dark in G-banding

What is euchromatin?

Chromatin that is gene-rich and stains light in G-banding

How do G-bands differ in colour and gene content?

Dark bands are heterochromatin and gene-poor; light bands are euchromatin and gene-rich

How are chromosome bands numbered?

According to an internationally agreed system of nomenclature

Why is band numbering important?

It allows precise description and comparison of chromosomal regions and abnormalities

What information is included in a chromosome band designation?

What information is included in a chromosome band designation?

How are chromosome bands numbered?

Bands are numbered starting from the centromere and moving outward toward the telomeres

What does p and q mean in chromosome banding?

p is the short arm of the chromosome; q is the long arm

What is meant by chromosome banding resolution?

The level of detail at which bands, sub-bands, and sub-sub-bands can be distinguished

What can be seen at the lowest banding resolution?

Only a few major bands, such as p1 and p2

What becomes visible at higher banding resolutions?

Sub-bands within major bands, which are numbered again from centromere to telomere

What additional detail can be seen at very high resolution?

Sub-sub-bands within sub-bands

Why is the chromosome band designation system important?

It allows accurate naming of chromosomal aberrations and identification of gene loci

What does the band designation 1p31 mean?

Chromosome 1, short arm (p), region 3, band 1

How are sub-bands written in chromosome nomenclature?

A decimal point is added after the band designation, followed by the sub-band number (e.g. 1p31.2)

How are sub-sub-bands written?

By adding an additional number without extra punctuation (e.g. 1p31.21)

What is the first rule when writing a karyotype?

The total number of chromosomes, including sex chromosomes, is written first, followed by a comma

How are sex chromosomes written in a normal karyotype?

As XX or XY (e.g. 46,XX or 46,XY)

How are autosomes written in a normal karyotype?

They are not listed individually unless abnormal

How are chromosomal abnormalities listed in a karyotype?

Sex chromosome abnormalities are listed first, followed by autosomal abnormalities in numerical order

What does the karyotype 46,XX indicate?

A female with 46 chromosomes and no detectable chromosomal abnormalities

What does the karyotype 46,XY indicate?

A male with 46 chromosomes and no detectable chromosomal abnormalities

What does the karyotype 47,XX,+21 indicate?

A female with trisomy 21 (Down syndrome)

What does t(X;13)(p27;q12) indicate?

A translocation between the X chromosome at band p27 and chromosome 13 at band q12

What does inv(10)(p13;q22) indicate?

An inversion on chromosome 10 between bands p13 and q22

How would multiple abnormalities be written in a karyotype?

After the chromosome number and sex chromosomes, abnormalities are listed sequentially according to nomenclature rules

What does the example 47,XX,t(X;13)(p27;q12),inv(10)(p13;q22),+21 represent?

A female with 47 chromosomes, a translocation between X and 13, an inversion on chromosome 10, and trisomy 21

What are the two main types of chromosomal aberrations?

Numerical (e.g., aneuploidy and polyploidy) and structural (e.g., deletions and translocations)

What is a numerical chromosomal aberration?

A change in the number of chromosomes, such as aneuploidy (loss or gain of a chromosome) or polyploidy (extra sets of chromosomes)

What is a structural chromosomal aberration?

Changes in chromosome structure, such as deletions, duplications, inversions, or translocations

What is a constitutional chromosomal aberration?

An abnormality present in all tissues, originating in the embryo, often from a gamete or zygote

What conditions are usually caused by constitutional chromosomal aberrations?

Inborn syndromes and rare anomalies present at birth; more frequent in abortuses and a common cause of reproductive failure

What is the difference between homogeneous and mosaic constitutional aberrations?

Homogeneous aberrations are in all cells (from the gamete), while mosaic aberrations occur in some cells (from a zygotic mutation)

What is an acquired chromosomal aberration?

An abnormality present only in one organ or tissue, often associated with cancer in that tissue

How do acquired chromosomal aberrations differ from constitutional ones?

They are tissue-specific and occur later in life, usually as part of disease like cancer, rather than being present in all cells from birth

What is a numerical chromosomal aberration?

A change in the number of whole chromosomes in a cell

What is polyploidy?

A condition where the whole set of chromosomes is multiplied