Chapter 8: Chromosome Variation
familial down syndrome
- About 4% of people with Down syndrome are not trisomic for a complete chromosome 21. Instead, they have 46 chromosomes, but an extra copy of part of chromosome 21 is attached to another chromosome through a translocation. This condition is termed familial Down syndrome because it has a tendency to run in families. The phenotypic characteristics of familial Down syndrome are the same as those of primary Down syndrome. - Familial Down syndrome arises in offspring whose parents are carriers of chromosomes that have undergone a Robertsonian translocation, most commonly between chromosome 21 and chromosome 14: the long arm of 21 and the short arm of 14 exchange places
primary down syndrome
- Approximately 92% of those who have Down syndrome have three full copies of chromosome 21 (and therefore a total of 47 chromosomes), a condition termed primary Down syndrome - Primary Down syndrome usually arises from spontaneous nondisjunction during egg formation: about 75% of the nondisjunction events that cause Down syndrome are maternal in origin, most arising in meiosis I. - Most children with Down syndrome are born to unaffected parents, and the failure of the chromosomes to divide has little hereditary tendency. Therefore, a couple who has conceived one child with primary Down syndrome has only a slightly higher risk of conceiving a second child with Down syndrome (compared with other couples of similar age who have not had any children with Down syndrome).
adjacent-2 segregation
- Leads to 4 genetically unbalanced gametes that are not viable because some chromosome segments are present in two copies, whereas others are missing. - Rare because the two homologous chromosomes usually separate in meiosis. - adjacent homologous chromosomes segregate into the same cell - unbalanced gametes N1 and N2 = normal chromosomes 1 and 2 T1 and T2 = translocated chromosomes 1 and 2 N1 and T1 have homologous centromeres (in both chromosomes, the centromere is between segments B and C); N2 and T2 have homologous centromeres (between segments M and N). - Normally, homologous centromeres separate and move toward opposite poles in anaphase I of meiosis. - N1 and T1 move toward one pole and T2 and N2 move toward the other
effects of aneuploidy
- Often dramatic phenotype - Most lethal in animals and plants - Because aneuploidy affects the number of gene copies but not their nucleotide sequences, the effects of aneuploidy are most likely due to abnormal gene dosage. Aneuploidy alters the dosage for some, but not all, genes, disrupting the relative concentrations of gene products and often interfering with normal development. - more than 30% of all conceptions are spontaneously aborted (miscarried), usually so early in development that the woman is not even aware of her pregnancy. Chromosome mutations are present in at least 50% of spontaneously aborted human fetuses, with aneuploidy accounting for most of them.
effects of duplication: heterozygotes vs homozygotes
- an individual that is homozygous for a duplication carries that duplication on both homologous chromosomes - an individual that is heterozygous for a duplication has one normal chromosome and one chromosome with the duplication. In heterozygotes, problems in chromosome pairing arise at prophase I of meiosis because the two chromosomes are not homologous throughout their length. The pairing and synapsis of homologous regions require that one or both chromosomes loop and twist so that these regions are able to line up. The appearance of this characteristic loop structure in meiosis is one way to detect duplications.
effects of translocation
- can physically link genes that were formerly located on different chromosomes. These new linkage relations may affect gene expression (a position effect), as genes translocated to new locations may come under the control of different regulatory sequences or other genes that affect their expression. - Second, the chromosome breaks that bring about translocations may take place within a gene and disrupt its function. Molecular geneticists have used these types of effects to map human genes.
Preparation and different staining techniques help to distinguish among chromosomes of similar size and shape.
- special preparation and staining of chromosomes with a dye called Giemsa reveals G bands, which distinguish areas of DNA that are rich in adenine-thymine (A-T) base pairs. - Q bands are revealed by staining chromosomes with quinacrine mustard and viewing the chromosomes under ultraviolet light; variation in the brightness of Q bands results from differences in the relative numbers of cytosine-guanine (C-G) and adenine-thymine base pairs.
types of aneuploidy
1. nullisomy 2. monosomy 3. trisomy 4. tetrasomy
there are two primary ways in which the structure of chromosomes can be altered
1. the total amount of genetic info in the chromosome can change - deficiencies/deletions (usually most harmful) - duplications 2. the genetic material remains the same but is rearranged - inversions - translocation
an individual with a reciprocal translocation usually produces ___ types of gametes.
4 - 2 are viable, 2 are nonviable - called semisterility
Williams-Beuren syndrome
A deletion of a tiny segment of chromosome 7 causes haploinsufficiency of the gene encoding elastin and a few other genes and leads to a condition known as Williams-Beuren syndrome, which is characterized by distinctive facial features, heart defects, high blood pressure, and cognitive impairments.
karyotype
A display of the chromosome pairs of a cell arranged by size and shape. - The complete set of chromosomes possessed by an organism is called its karyotype. An organism's karyotype is usually presented as a picture of metaphase chromosomes lined up in descending order of their size. Karyotypes are prepared from actively dividing cells, such as white blood cells, bone-marrow cells, or cells from meristematic tissues of plants. - After treatment with a chemical (such as colchicine) that prevents them from entering anaphase, the cells are chemically preserved. They are then burst open to release the chromosomes onto a microscope slide, and the chromosomes are stained and photographed.
adjacent-1 segregation
A pattern of chromosome segregation that can occur following reciprocal balanced translocation. Not viable because some chromosome segments are present in two copies, whereas others are missing - adjacent non-homologous chromosomes segregate into the same cell - unbalanced gametes N1 and N2 = normal chromosomes 1 and 2 T1 and T2 = translocated chromosomes 1 and 2 N1 and T1 have homologous centromeres (in both chromosomes, the centromere is between segments B and C); N2 and T2 have homologous centromeres (between segments M and N). - Normally, homologous centromeres separate and move toward opposite poles in anaphase I of meiosis. - N1 and T2 move toward one pole, and T1 and N2 move toward the other pole (homologous centromeres segregate to opposite poles)
alternate segregation
A pattern of chromosome segregation that can occur following reciprocal translocation that leads to the production of viable gametes. - chromsomes on opposite sides of the translocation cross segregate into the same cell - leads to balanced gametes N1 and N2 = normal chromosomes 1 and 2 T1 and T2 = translocated chromosomes 1 and 2 N1 and T1 have homologous centromeres (in both chromosomes, the centromere is between segments B and C); N2 and T2 have homologous centromeres (between segments M and N). - Normally, homologous centromeres separate and move toward opposite poles in anaphase I of meiosis. - N1 and N2 move toward one pole, and T1 and T2 move toward the opposite pole (homologous centromeres segregate to opposite poles)
Notch mutation in Drosophila
A series of X-linked wing mutations in Drosophila are known as Notch mutations. These mutations often result from chromosome deletions. - Notch deletions behave in a dominant manner: when heterozygous for a Notch deletion, a fly has wings that are notched at the tips and along the edges. The Notch gene is therefore haploinsufficient. - Females that are homozygous for a Notch deletion (or males that are hemizygous) die early in embryonic development. - The Notch gene, which is deleted in Notch mutants, encodes a receptor that normally transmits signals received from outside the cell to the cell's interior and is important in fly development. The deletion acts as a recessive lethal because the loss of all copies of the Notch gene prevents normal development.
How does chromosome duplication alter the phenotype?
After all, gene sequences are not altered by duplications, and no genetic information is missing; the only change is the presence of additional copies of normal sequences. - The answer to this question is not well understood, but the effects are most likely due to imbalances in the amounts of gene products (abnormal gene dosage). - The amount of a particular protein synthesized by a cell is often directly related to the number of copies of its corresponding gene: an individual organism with three functional copies of a gene often produces 1.5 times as much of the protein encoded by that gene as an individual with two copies. - Because developmental processes require the interaction of many proteins, they often depend critically on proper gene dosage. If the amount of one protein increases while the amounts of others remain constant, problems can result
Bar mutation in fruit flies
Among fruit flies, for example, a fly with the Bar mutation has a reduced number of facets in the eye, making the eye smaller and bar shaped instead of oval. - results from a small duplication on the X chromosome that is inherited as an incompletely dominant, X-linked trait: - heterozygous female flies have somewhat smaller eyes (the number of facets is reduced) - in homozygous female and hemizygous male flies, the number of facets is greatly reduced. - Occasionally, a fly carries three copies of the Bar duplication on its X chromosome; in flies with this mutation, termed double Bar, the number of facets is extremely reduced
double trisomic
An individual that has an extra copy of each of two different (nonhomologous) chromosomes. This condition is represented as 2n + 1 + 1
break point effect
An inversion break point occurs in a vital gene
position effect
An inversion may break a gene into two parts, with one part moving to a new location and destroying the function of that gene. Even when the chromosome breaks lie between genes, phenotypic effects may arise from the inverted gene order (posiiton affects gene expression/regulation). - Many genes are regulated in a position-dependent manner; if their positions are altered by an inversion, their expression may be altered, an outcome referred to as a position effect. - For example, when an inversion moves a wild-type allele (which normally encodes red eyes) at the white locus in Drosophila to a chromosomal region that contains highly condensed and inactive chromatin, the wild-type allele is not expressed in some cells, resulting in an eye consisting of red and white spots.
importance of duplication in evolution
Chromosome duplications are one way in which new genes evolve. In many cases, existing copies of a gene are not free to vary because they encode a product that is essential to development or function. However, after a chromosome undergoes duplication, extra copies of genes within the duplicated region are present. The original copy can provide the essential function, whereas an extra copy from the duplication is free to undergo mutation and change. Over evolutionary time, the extra copy may acquire enough mutations to assume a new function that benefits the organism.
structural variants
Chromosome rearrangements and copy-number variations
Wolf-Hirschhron syndrome
Deletion of part of the short arm of chromosome 4 results in another human disorder, Wolf-Hirschhorn syndrome, which is characterized by seizures, severe intellectual disability, and delayed growth.
effect of unequal crossing over
Duplications and deletions often arise from unequal crossing over, in which chromosomes misalign during crossing over. - Unequal crossing over is frequently the cause of red-green color blindness in humans
how can aneuploidy arise?
First, a chromosome may be lost in the course of mitosis or meiosis if, for example, its centromere is deleted. Loss of the centromere prevents the spindle microtubules from attaching, so the chromosome fails to move to the spindle pole and does not become incorporated into a nucleus after cell division. Second, the small chromosome generated by a Robertsonian translocation may be lost in mitosis or meiosis. Third, aneuploidy may arise through nondisjunction, the failure of homologous chromosomes or sister chromatids to separate in meiosis or mitosis
globe mutation
For example, the globe mutation (which produces a globe-shaped seedcase) was dominant but was inherited primarily from the female parent. When globe mutants self-fertilized, only 25% of the progeny had the globe phenotype. If the globe mutation were strictly dominant, Blakeslee should have seen 75% of the progeny with the trait (see Chapter 3), so the 25% that he observed was unusual. Blakeslee isolated 12 different mutants that exhibited peculiar patterns of inheritance. Eventually, John Belling demonstrated that these 12 mutants were in fact trisomics. D. stramonium has 12 pairs of chromosomes (2n = 24), and each of the 12 mutants was trisomic for a different chromosome pair.
inversion: anaphase I (dicentric bridge)
In anaphase I of meiosis, the centromeres are pulled toward opposite poles, and the two homologous chromosomes separate. This action stretches the dicentric chromatid across the center of the nucleus, forming a structure called a dicentric bridge. - Eventually, the dicentric bridge breaks as the two centromeres are pulled farther apart. Spindle microtubules do not attach to the acentric fragment, so that fragment does not segregate to a spindle pole and is usually lost when the nucleus re-forms.
aneuploidy
In aneuploidy, the number of chromosomes is altered: one or more individual chromosomes are added or deleted.
cri-du-chat syndrome
In humans, a deletion on the short arm of chromosome 5 is responsible for cri-du-chat syndrome. - The name (French for "cry of the cat") derives from the peculiar, catlike cry of infants with this syndrome. - A child who is heterozygous for this deletion has a small head, widely spaced eyes, and a round face, and is intellectually disabled. - genetic constitution designated as 46,5p (deletion of short arm of chromosome 5)
individuals heterozygous for deletions
In individuals heterozygous for deletions, the normal chromosome must loop out during the pairing of homologs in prophase I of meiosis to allow the homologous regions of the two chromosomes to align and undergo synapsis. This looping out generates a structure that looks very much like that seen in individuals heterozygous for duplications.
A major exception to the relation between gene number and gene dosage pertains to genes on the mammalian X chromosome.
In mammals, X-chromosome inactivation ensures that males (who have a single X chromosome) and females (who have two X chromosomes) receive the same functional dosage for X-linked genes (see Chapter 4 for further discussion of X-chromosome inactivation). Because additional X chromosomes in mammals are inactivated, we might expect that aneuploidy of the sex chromosomes would be less detrimental in these animals.
polyploidy
In polyploidy, one or more complete sets of chromosomes are added. - A polyploid is any organism that has more than two sets of chromosomes (3n, 4n, 5n, or more).
inversion: meiosis II
In the second division of meiosis, the sister chromatids separate, and four gametes are produced (see Figure 8.14e). Two of the gametes contain the original, nonrecombinant chromosomes (AB•CDEFG and AB•EDCFG). The other two gametes contain recombinant chromosomes that are missing some genes; these gametes will not produce viable offspring. - Thus, no recombinant progeny result when crossing over takes place within a paracentric inversion. - The key is to recognize that when crossing over takes place, the resulting recombinant gametes are not viable, so no recombinant progeny are observed.
When a translocation carrier produces gametes, the translocation chromosome segregates in one of three different ways. First, it may separate from the normal chromosomes 14 and 21 in anaphase I of meiosis
In this type of segregation, half of the gametes produced will have the translocation chromosome and no other copies of chromosomes 21 and 14; the fusion of such a gamete with a normal gamete will give rise to a translocation carrier. The other half of the gametes produced by this first type of segregation will be normal, each with a single copy of chromosomes 21 and 14, and will result in offspring with a normal set of chromosomes.
translocation carriers
Individual organism heterozygous for a chromosome translocation. - 45 chromosomes - Although they possess only 45 chromosomes, their phenotypes are normal because they have two copies of the long arms of chromosomes 14 and 21, and apparently the short arms of these chromosomes (which are lost) carry no essential genetic information. Although translocation carriers have a completely normal phenotype, they have an increased chance of producing children with Down syndrome. - only three of the six types of gametes that can be produced by a translocation carrier will result in the birth of a baby, and theoretically, these gametes should arise with equal frequency. One-third of the offspring of a translocation carrier should be translocation carriers like their parent, one-third should have familial Down syndrome, and one-third should have a normal set of chromosomes.
paracentric inversions
Inversions that do not include the centromere, such as AB•CFEDG (para meaning "next to")
Recombination is also reduced within a pericentric inversion
No dicentric bridges or acentric fragments are produced, but the recombinant chromosomes have too many copies of some genes and no copies of others, so gametes that receive the recombinant chromosomes cannot produce viable progeny.
uniparental disomy
Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent. - Many cases of uniparental disomy probably originate as trisomies. Although most autosomal trisomies are lethal, a trisomic embryo can survive if one of the three chromosomes is lost early in development. If, just by chance, the two remaining chromosomes are both from the same parent, uniparental disomy results.
what may account for the high levels of aneuploidy seen in human conceptions that originate in oogenesis
Research of crossover formation in humans demonstrates that the process of crossover maturation in females is often inefficient compared to that in males, leading to fewer mature crossovers in females and, among those that do occur, more crossovers that are likely to lead to missegregation of chromosomes during meiosis.
Like deletions, the phenotypic consequences of duplications tend to be correlated to...
SIZE (however, duplications tend to have less harmful effects than deletions of comparable size)
dicentric bridge
Structure produced when the two centromeres of a dicentric chromatid are pulled toward opposite poles, stretching the dicentric chromosome across the center of the nucleus. Eventually, the dicentric bridge breaks as the two centromeres are pulled apart. - occurs in paracentric inversion
inversion: prophase I (dicentric and acentric chromatids)
Suppose that an individual is heterozygous for an inversion, with one wild-type, nonmutated chromosome (AB•CDEFG) and one inverted chromosome (AB•EDCFG). In prophase I of meiosis, an inversion loop forms, allowing the homologous sequences to pair up (see Figure 8.14b). If a single crossover takes place in the inverted region (between segments C and D, an unusual structure results (see Figure 8.14c). The two outer chromatids, which did not participate in crossing over, contain original, nonrecombinant gene sequences. - The two inner chromatids, which did participate in crossing over, are highly abnormal: each has two copies of some genes and no copies of others. - Furthermore, one of the four chromatids now has two centromeres, and is therefore referred to as a dicentric chromatid; the other lacks a centromere and is an acentric chromatid.
The effect of a translocation on chromosome segregation in meiosis depends on the nature of the translocation. Consider what happens in an individual heterozygous for a reciprocal translocation.
Suppose that the original chromosomes are AB•CDEFG and M•NOPQRST (designated N1 and N2, respectively, for normal chromosomes 1 and 2) and that a reciprocal translocation takes place, producing chromosomes AB•CDQRST and M•NOPEFG (designated T1 and T2, respectively, for translocated chromosomes 1 and 2). An individual heterozygous for this translocation would possess one normal copy and one translocated copy of each chromosome. Each of these chromosomes contains segments that are homologous to segments of two other chromosomes. Thus, when the homologous segments pair in prophase I of meiosis, crosslike configurations consisting of all four chromosomes form
telocentric
The centromere is at or very near the end of the chromosome
submetacentric
The centromere is displaced toward one end, creating a long arm and a short arm. (On human chromosomes, the short arm is designated by the letter p and the long arm by the letter q.)
metacentric
The centromere is located approximately in the middle, so the chromosome has two arms of equal length
acrocentric
The centromere is near one end, producing a long arm and a knob, or satellite, at the other end.
trisomy
The gain of a single chromosome, represented as 2n + 1. A human trisomic zygote has 47 chromosomes. The gain of a chromosome means that there are three homologous copies of one chromosome. Most cases of Down syndrome, discussed later in this section, result from trisomy of chromosome 21.
When a translocation carrier produces gametes, the translocation chromosome segregates in one of three different ways. In the third type of segregation, the translocation chromosome and the normal copy of chromosome 14 segregate together
This pattern is presumably rare because the two centromeres are both derived from chromosome 14 and usually separate from each other. All the gametes produced by this process are abnormal: half result in monosomy 14 and the other half result in trisomy 14. All are spontaneously aborted.
When a translocation carrier produces gametes, the translocation chromosome segregates in one of three different ways. Alternatively, the translocation chromosome may separate from chromosome 14 and pass into the same cell with the normal chromosome 21
This type of segregation produces abnormal gametes only; half will have two functional copies of chromosome 21 (one normal and one attached to chromosome 14) and the other half will lack chromosome 21. If a gamete with the two functional copies of chromosome 21 fuses with a normal gamete carrying a single copy of chromosome 21, the resulting zygote will have familial Down syndrome. If a gamete lacking chromosome 21 fuses with a normal gamete, the resulting zygote will have monosomy 21 and will be spontaneously aborted.
reverse duplication
When the duplication is inverted
chromosome inversion
a chromosome segment is inverted—turned 180 degrees - If a chromosome originally had segments AB•CDEFG, then chromosome AB•CFEDG represents an inversion that includes segments DEF. - For an inversion to take place, the chromosome must break in two places. - Individual organisms with inversions have neither lost nor gained any genetic material; only the DNA sequence has been altered. Nevertheless, these mutations often have pronounced phenotypic effects.
chromosome duplication
a mutation in which part of the chromosome has been doubled. - Consider a chromosome with segments AB•CDEFG, in which • represents the centromere. A duplication might include the EF segments, giving rise to a chromosome with segments AB•CDEFEFG (where the underlined letters represent the part of the chromosome that has changed). - two types of duplication: tandem and displaced
copy-number variation
a segment of DNA that varies in copy number among members of same species - They include duplications and deletions that range in length from thousands of base pairs to several million base pairs. Many of these variants include at least one gene and may encompass several.
a gene is haploinsufficient when
a single copy of a gene is not sufficient to produce a wild-type phenotype
down syndrome
also known as trisomy 21, is the most common autosomal aneuploidy in humans
trisomy 8
arises with a frequency ranging from about 1 in 25,000 to 1 in 50,000 live births. This aneuploidy is characterized by intellectual disability, contracted fingers and toes, low-set malformed ears, and a prominent forehead. Most individuals born with this condition are mosaics, having some cells with three copies of chromosome 8 and other cells with the usual two copies. Complete trisomy 8, in which all cells in the body have three copies of chromosome 8, usually results in spontaneous abortion.
interpret the following chromosome: 9q34
chromosome 9, long arm, band 34
chromosome rearrangement
chromosome mutations that change the structure of individual chromosomes. - The four basic types of rearrangements are duplications, deletions, inversions, and translocations. - Many of these chromosome rearrangements originate when double-stranded breaks occur in the DNA molecule found within a chromosome. - If the two broken ends are rejoined correctly, the original chromosome is restored, and no chromosome rearrangement results. Sometimes the wrong ends are connected, however, leading to a chromosome rearrangement. - Chromosome rearrangements can also arise through errors in crossing over or when crossing over occurs between repeated DNA sequences.
euploidy
complete haploid sets of chromosomes are present (multiples of n)
segmental duplications (intra- vs inter-)
defined as duplications greater than a thousand base pairs (bp) in length. - Most segmental duplications are intrachromosomal duplications (i.e., the two copies are found on the same chromosome) - others are interchromosomal duplications (the two copies are found on different chromosomes).
terminal deletion
deletion in which a segment is lost from the end of a linear chromosome
The phenotypic consequences of a deletion
depend on SIZE of deletion and TYPE of gene - If the deletion includes the centromere, then the chromosome will not segregate in meiosis or mitosis and will usually be lost. - Many deletions are lethal in the homozygous state because all copies of any essential genes located in the deleted region are missing. - Even individuals heterozygous for a deletion may have multiple defects for three reasons. First, the heterozygous condition may produce imbalances in the amounts of gene products similar to those produced by extra gene copies. Second, normally recessive mutations on the homologous chromosome lacking the deletion may be expressed when the wild-type allele has been deleted (and is no longer present to mask the recessive allele's expression)
duplications and gene families
duplication leads to genetic variation and eventually evolution. this can ultimately lead to the formation of gene families: - a gene family consists of two or more genes that are similar to each other - members of a gene family have similar but distinct functions, derived from a single ancestor (homologous genes) - accumulate genes independent of each other - example: different types of hemoglobin (embryonic, myoglobin)
trisomy 18
edward's syndrome - arises with a frequency of approximately 1 in 8000 live births. Babies with Edwards syndrome have severe intellectual disability, low-set ears, a short neck, deformed feet, clenched fingers, heart problems, and other disabilities. Few live for more than a year after birth.
translocation
entails the movement of genetic material between nonhomologous chromosomes or within the same chromosome. - should not be confused with crossing over, in which there is an exchange of genetic material between homologous chromosomes - non-reciprocal and repiprocal
fragile-X syndrome
exhibits X-linked inheritance and arises with a frequency of about 1 in 5000 male births - has been shown to result from an increase in the number of repeats of a CGG trinucleotide, a type of mutation known as expanding nucleotide repeats. - In the case of fragile-X syndrome, the increased copies of the CGG trinucleotide occur within and disrupt a gene that encodes fragile X mental retardation protein (FMRP), which regulates the translation of other proteins and plays a role in the development of neural synapses.
pseudominance
expression of recessive allele when balancing dominant allele is deleted - it is an indication that one of the homologous chromosomes has a deletion.
Double crossovers in which both crossovers are on the same two strands (two-strand double crossovers) result in _______ recombinant chromosomes.
functional (Thus, even though the overall rate of recombination is reduced within an inversion, some viable recombinant progeny may still be produced through two-strand double crossovers.)
non-reciprocal translocation
genetic material moves from one chromosome to another without any reciprocal exchange - Consider the following two nonhomologous chromosomes: AB•CDEFG and MN•OPQRS. If chromosome segment EF moves from the first chromosome to the second without any transfer of segments from the second chromosome to the first, a nonreciprocal translocation has taken place, producing chromosomes AB•CDG and MN•OPEFQRS
trisomy 13
has a frequency of about 1 in 15,000 live births and produces features that are collectively known as Patau syndrome. Characteristics of this condition include severe intellectual disability, a small head, a sloping forehead, small eyes, a cleft lip and palate, extra fingers and toes, and numerous other problems. About half of the children with trisomy 13 die within the first month of life, and 95% die by the age of three
double tetrasomic
has two extra pairs of homologous chromosomes (2n + 2 + 2).
double monosomic
has two fewer nonhomologous chromosomes than normal (2n − 1 − 1)
orthologs
homologous genes separated by a speciation event
paralogs
homologous genes within a single species
effects of duplications: crossover
if a crossover occurs, nonallelic homologous recombination results (not recombining at proper place)
Most cases of Down syndrome and other types of aneuploidy in humans arise from maternal nondisjunction, and the frequency of aneuploidy ________ with maternal age
increases
pericentric inversions
inversions that include the centromere, such as ADC•BEFG (peri meaning "around")
q
long arm of chromosome
when an individual is homozygous for a particular inversion
no special problems arise in meiosis, and the two homologous chromosomes can pair and separate normally
unequal crossing over in red-green color blindness
perception of color is affected by red and green opsin genes, which are found on the X chromosome and are 98% identical in their DNA sequence. Most people with normal color vision have one red opsin gene and one green opsin gene (although some people have more than one copy of each). Occasionally, two paired X chromosomes in a female do not align properly in prophase I, and unequal crossing over takes place. The unequal crossing over produces one chromosome with an extra opsin gene and one chromosome that is missing an opsin gene. When a male inherits the chromosome that is missing one of the opsin genes, red-green color blindness results.
PLK4 gene
plays a role in regulating the centriole (see Chapter 2), the disruption of which can lead to failure of the chromosomes to separate properly in mitosis. Interestingly, this genetic variant occurs at high frequencies in many human populations, and some evidence suggests it has been favored by natural selection, but why it might have been favored by natural selection is still unclear.
Why maternal age is associated with nondisjunction
primary oocytes may remain suspended in diplotene for many years before ovulation takes place and meiosis recommences. Cohesin components of the spindle and other structures required for proper chromosome segregation may break down during the long arrest of meiosis, leading to more aneuploidy in children born to older mothers. - this added length of time, as a result, may contribute to an increased frequency of nondisjunction
reciprocal translocation
reciprocal exchange of segments between two nonhomologous chromosomes - also called balanced translocations because it is a rearrangement of the genetic material, not a change in the total amount - A reciprocal translocation between chromosomes AB•CDEFG and MN•OPQRS might give rise to chromosomes AB•CDQRS and MN•OPEFG.
The most common aneuploidies seen in living humans are those that involve the...
sex chromosomes (e.g. Turner and Klinefelter syndromes)
p
short arm of chromosome
fragile sites
sites on chromosomes that develop constrictions or gaps when the cells are grown in culture and that are prone to breakage under certain conditions. - More than 100 fragile sites have been identified on human chromosomes. - Fragile sites are often replicated late in S phase. At these sites, the enzymes that replicate DNA may stall while unwinding of the DNA continues (see Chapter 12), leading to long stretches of DNA that are unwound and vulnerable to breakage.
tandem duplication
the duplicated segment is immediately adjacent to the original segment
displaced duplication
the duplicated segment is located some distance from the original segment, either on the same chromosome or on a different one
tetrasomy
the gain of two homologous chromosomes, represented as 2n + 2. A human tetrasomic zygote has 48 chromosomes. Tetrasomy is not the gain of any two extra chromosomes but rather the gain of two homologous chromosomes, so that there are four homologous copies of a particular chromosome.
when an individual is heterozygous for an inversion
the gene order of the two homologs differs, and the homologous sequences can align and pair only if the two chromosomes form an inversion loop in order to synpase properly - Individuals heterozygous for inversions also exhibit reduced recombination among genes located in the inverted region. When crossing over takes place, the outcome is abnormal gametes that do not give rise to viable offspring, and thus no recombinant progeny are observed. - may be phenotypically normal
Deletions frequently accompany translocations. In a Robertsonian translocation...
the long arms of two acrocentric chromosomes become joined to a common centromere through a translocation, generating a metacentric chromosome with two long arms and another chromosome with two very short arms. - breaks occur at the extreme ends of the short arms of two non-homologous acrocentric chromosomes - the larger fragments fuse at their centromeric regions to form a single chromosome which is metacentric/submetracentric - The smaller chromosome (acentric fragment) is often lost because very small chromosomes do not have enough mass to segregate properly during mitosis and meiosis. The result is an overall reduction in chromosome number. - As we will see, Robertsonian translocations are the cause of some cases of Down syndrome
chromosome deletion
the loss of a chromosome segment. - A chromosome with segments AB•CDEFG that undergoes a deletion of segment EF would generate the mutated chromosome AB•CDG.
monosomy
the loss of a single chromosome, represented as 2n − 1. A human monosomic zygote has 45 chromosomes.
nullisomy
the loss of both members of a homologous pair of chromosomes. It is represented as 2n − 2, where n refers to the haploid number of chromosomes. Thus, among humans, who normally possess 2n = 46 chromosomes, a nullisomic zygote has 44 chromosomes.
familial down syndrome and robertsonian translocation
translocation most commonly occurs between chromosome 21 and chromosome 14: the long arm of 21 and the short arm of 14 exchange places - This exchange produces one chromosome that includes the long arms of chromosomes 14 and 21 and another, very small chromosome that consists of the short arms of chromosomes 21 and 14. - The small chromosome (two very short arms) is generally lost after several cell divisions. - Although exchange between chromosomes 21 and 14 is the most common cause of familial Down syndrome, the condition can also be caused by translocations between 21 and other chromosomes, such as 15.
Crossing over within an inversion in an individual that is heterozygous for a pericentric or paracentric inversion leads to _______ gametes and _______ progeny.
unbalanced ; non-recombinant
interstitial deletion
when an internal segment is lost from a linear chromosome
simple translocation
when one piece of a chromosome becomes attached to a different chromosome (occurs in one direction) - unbalanced translocations - associated with phenotyppic abnormalities and even lethality - e.g. familial down syndrome
