Chromosomes

Cytogenetics

• A subdiscipline within genetics

• Focuses on chromosome variations

• Abnormal number of copies of genes or chromosomes can lead to genetic abnormalities

• Human genome sequence information is used to identify genes that contribute to the chromosome-related syndromes

Portrait of a Chromosome

• Primarily DNA and protein• Described by size and shape• Heterochromatin (dark)• Euchromatin (light)• Contains:

– Telomeres– Origin of replication sites– Centromere

Chromosomes

• Heterochromatin is darkly staining, contains mostly repetitive DNA

• Euchromatin contains more protein encoding genes

• Telomeres are chromosome tips composed of many repeats of TTAGGG and shorten with each cell division

• Centromere is the largest constriction of the chromosome and where spindle fibers attach

Centromere Position• At tip telocentric• Close to end acrocentric• Displaced from center submetacentric

– Long arm q– Short arm p

• At midpoint metacentric

Karyotype

• Chromosomal chart

• Chromosomes arranged by size and structure

• Arranged by largest to smallest

Visualizing Chromosomes

Fetal tissue: amniocentesis

chorionic villi sampling

fetal cell sorting

Adult tissue: blood (white blood cells)

cheek swab (buccal cells)

skin cells

tissue biopsy

Amniocentesis

Figure 13.5a

Chorionic Villi Sampling

Figure 13.5b

Fetal Cell Sorting

Figure 13.5c

FISHing

• Fluorescence in situ hybridization– in situ =in tissue– in vivo =in living organism– in vitro =in a dish

• Uses a fluorescent probe to detect specific sequences of DNA

Chromosomal Abnormalities

Abnormal Chromosome # -Polyploidy

• Polyploidy– An entire extra set of

chromosome

• Example: Triploidy

– One egg fertilized by 2 sperm

OR

– A diploid egg fertilized by one sperm

– A diploid sperm fertilizes an egg

Abnormal Chromosome # -Aneuploidy

• Missing a single chromosome (monosomy)– OR -

• Having one extra chromosome (trisomy)

• Euploid =“good set” • Aneuploid =“not good set”

• Caused by nondisjunction during meiosis

Nondisjunction at Meiosis I

Nondisjunction at Meiosis II

Nondisjunction at Mitosis

• Results in a mosaic– Some cell populations are

affected while others are not

• Severity of symptoms depends on how early in development the nondisjunction occurs.

Autosomal Aneuploids

• Usually lethal

• Those that survive often have mental retardation

• Most common for chromosomes 13, 18, and 21. Why?

Trisomy 21

• October is Down Syndrome Awareness Month!

Table 13.6

Figure 13.7

Oogenesis

Before birthArrested in Prophase I

After puberty (each month)Arrested in Metaphase II

Upon fertilization

Trisomy 18

• Edward syndrome• Severe physical and mental

disabilities• Development stops at the 6

month level• Oddly clenched fists• Low-set ears• Small mouth• Unusual or absent fingerprints• Liver and heart problems

Trisomy 13

• Patau syndrome• Fusion of the eyes or a

small or absent eye• Cleft lip and palate• Extra fingers and toes• Mental retardation

Sex Chromosome Aneuploidy

Sex Chromosome Aneuploids: Female

• Turner syndrome (XO)– Delayed puberty– 99% are not born– Infertile

• Triplo-X (XXX)– Tall stature– Menstrual abnormalities– All but 1 X is inactivated

Sex Chromosome Aneuploids: Male

• Klinefelter Syndrome (XXY)– Sexually underdeveloped

• Small testes• Sparse facial and pubic hair

– Long arms and legs and big feet and hands

– May develop breast tissue– Often infertile

Sex Chromosome Aneuploids: Male

• XXYY Syndrome– Slightly delayed childhood development– Behavioral problems

• ADD, OCD, and learning disabilities

– Leg ulcers due to poor circulation– Sexual development is delayed– Testes do not descend– Infertile– Abnormal (YY) sperm AND abnormal (XX) egg

Sex Chromosome Aneuploids: Male

• Jacobs Syndrome (XYY)

• 1/1000 males has an extra Y

• 96% of XYY males are normal

• Tall height and acne

• Criminals with chromosomal abnormalities tend to have XYY

Abnormal Chromosome Structure

• Deletion =missing genetic material– Can range in size (the

more genes deleted, the worse the phenotype)

• Duplication =a region of the chromosome where genes are repeated

• Inversion =the DNA sequence in a region of the chromosome is inverted

• Translocation =a piece of the chromosome is moved to another chromosome

Translocation• Nonhomologous chromosome exchange segments

Two major types:• Robertsonian translocation • Two nonhomologous acrocentric chromosomes break at the centromere and long arms fuse. The short arms are often lost. • 5% of Down syndrome results from a Robertsonian translocation between chr 21 and chr 14.• Reciprocal translocation • Two nonhomologous chromosomes exchange a portion of their chromosome arms.

Segregation of a Robertsonian Translocation

Reciprocal Translocation

• Exchange of material from one chromosome arm to another • Some individuals carry a translocation but are not missing any genetic material unless a translocation breakpoint interrupts a gene

Inversions

• Inverted chromosomes have a region flipped in orientation

• 5-10% cause health problems probably due to disruption of genes at the breakpoints

• Inversions may impact meiotic segregation • Two types of inversions occur:• Paracentric

– inverted region does NOT include centromere• Pericentric

– inverted region includes centromere

Segregation of a Paracentric Inversion

Figure 13.21

Segregation of a Pericentric Inversion

Figure 13.22

Isochromosomes

• Chromosomes with identical arms • Form when centromeres divide along the incorrect plane during meiosis

Figure 13.23

Ring Chromosomes

• Chromosomes shaped like a ring • Occur in 1 in 25,000 conceptions• May arise when telomeres are lost

and sticky chromosome end fuse– Radiation exposure