Evans syndrome: clinical perspectives, biological insights and ...
Chromosomal Abnormalities
Chromosomal abnormalities, alterations and aberrations are at the root of many inherited diseases and traits. Chromosomal abnormalities often give rise to birth defects and congenital conditions that may develop during an individual's lifetime. Examining the karyotype of chromosomes (karyotyping) in a sample of cells can allow detection of a chromosomal abnormality and counselling can then be offered to parents or families whose offspring are at risk of growing up with a genetic disorder.
Types of chromosomal abnormalityA chromosomal abnormality may be numerical or structural and examples are described below:
Numerical abnormalitiesThe normal human chromosome contains 23 pairs of chromosomes, giving a total of 46 chromosomes in each cell, called diploid cells. A normal sperm or egg cell contains only one half of these pairs and therefore 23 chromosomes. These cells are called haploid.
The euploid state describes when the number of chromosomes in each cell is some multiple of n, which may be 2n (46, diploid), 3n (69, triploid) 4n (92, tetraploid) and so on. When chromosomes are present in multiples beyond 4n, the term polyploid is used.
Aneuploidy refers to the presence of an extra chromosome or a missing chromosome and is the most common form of chromosomal abnormality. In the case of Down's syndrome or Trisomy 21, there is an additional copy of chromosome 21 and therefore 47 chromosomes. Turner's syndrome on the other hand arises from the absence of an X chromosome, meaning only 45 chromosomes are present.
Occasionally, aneuploid and regular diploid cells exist simultaneously and this is called mosaicism. The condition involves two or more different cell populations from a single fertilized egg. Mosaicism usually involves the sex chromosomes, although it can involve autosomal chromosomes.
In contrast to mosaicism, a condition called chimaerism occurs when different cell lines derived from more than one fertilized egg are involved.
Structural abnormalitiesStructural abnormalities occur when the chromosomal morphology is altered due to an unusual location of the centromere and therefore abnormal lengths of the chromosome's short (p) and long arm (q).
Some of the most common chromosomal abnormalities include:
Tethering Of Shattered Chromosomal Fragments Paves Way For New Cancer Therapies
Healthy cells work hard to maintain the integrity of our DNA, but occasionally, a chromosome can get separated from the others and break apart during cell division. The tiny fragments of DNA then get reassembled in random order in the new cell, sometimes producing cancerous gene mutations.
This chromosomal shattering and rearranging is called "chromothripsis" and occurs in the majority of human cancers, especially cancers of the bones, brain and fatty tissue. Chromothripsis was first described just over a decade ago, but scientists did not understand how the floating pieces of DNA were able to be put back together.
In a study published in Nature, researchers at University of California San Diego have answered this question, discovering that the shattered DNA fragments are actually tethered together. This allows them to travel as one during cell division and be re-encapsulated by one of the new daughter cells, where they are reassembled in a different order.
"It's similar to a smashed car windshield, where the safety glass is designed to keep all of the broken pieces in place," said senior study author Don W. Cleveland, Ph.D., Distinguished Professor and chair of the Department of Cellular and Molecular Medicine at UC San Diego School of Medicine. "What we've done here is find the safety glass and identify several of its core components, which we can now explore as therapeutic targets."
When chromosomes break and rearrange themselves, this can initiate or exacerbate cancer in several ways. For example, if a tumor suppressor gene is broken in the process, the cell will become more vulnerable to tumor formation.
In other cases, genes that aren't usually close to each other on the chromosome can suddenly be stitched together to produce a new oncogenic fusion protein. During chromothripsis, many such changes occur simultaneously, rather than gradually, thus accelerating cancer development or its resistance to therapy.
Now that the researchers had identified an early step in this process—the tethering of shattered DNA fragments—they wondered if they could stop it. By destroying the tether, they might prevent the rearranged chromosomes from forming, thereby reducing the number of cells potentially carrying cancerous mutations.
To do this, postdoctoral fellow and first author of the study Prasad Trivedi, Ph.D., engineered a modified version of one of the tether proteins so that he could induce its destruction on demand. When he did so, the tether disintegrated, the DNA fragments did not cluster and the resulting cells showed reduced survival.
The authors suggest that the proteins in this tether complex, particularly cellular inhibitor of PP2A (CIP2A), may now be an attractive therapeutic target for chromosomally unstable tumors.
"The process of chromosomal care and repair contributes to cancer in many ways, so the more we understand how it works, the better we can fine-tune it to treat cancer," said Cleveland.
More information: Prasad Trivedi et al, Mitotic tethering enables inheritance of shattered micronuclear chromosomes, Nature (2023). DOI: 10.1038/s41586-023-06216-z
Citation: Tethering of shattered chromosomal fragments paves way for new cancer therapies (2023, June 15) retrieved 14 July 2023 from https://medicalxpress.Com/news/2023-06-tethering-shattered-chromosomal-fragments-paves.Html
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Butterflies And Moths Share Ancient 'blocks' Of DNA
Butterflies and moths share "blocks" of DNA dating back more than 200 million years, new research shows.
Scientists from the Universities of Exeter (UK), Lübeck (Germany) and Iwate (Japan) devised a tool to compare the chromosomes (DNA molecules) of different butterflies and moths.
They found blocks of chromosomes that exist in all moth and butterfly species, and also in Trichoptera -- aquatic caddisflies that shared a common ancestor with moths and butterflies some 230 million years ago.
Moths and butterflies (collectively called Lepidoptera) have widely varying numbers of chromosomes -- from 30 to 300 -- but the study's findings show remarkable evidence of shared blocks of homology (similar structure) going back through time.
"DNA is compacted into individual particles or chromosomes that form the basic units of inheritance," said Professor Richard ffrench-Constant, from the Centre for Ecology and Conservation on Exeter's Penryn Campus in Cornwall.
"If genes are on the same 'string', or chromosome, they tend to be inherited together and are therefore 'linked'.
"However, different animals and plants have widely different numbers of chromosomes, so we cannot easily tell which chromosomes are related to which.
"This becomes a major problem when chromosome numbers vary widely -- as they do in the Lepidoptera.
"We developed a simple technique that looks at the similarity of blocks of genes on each chromosome and thus gives us a true picture of how they change as different species evolve.
"We found 30 basic units of 'synteny' (literally meaning 'on the same string' where the string is DNA) that exist in all butterflies and moths, and go back all the way to their sister group the caddisflies or Trichoptera."
Butterflies are often seen as key indicators of conservation, and many species worldwide are declining due to human activity.
However, this study shows that they are also useful models for the study of chromosome evolution.
The study improves scientific understanding of how moth and butterfly genes have evolved and, importantly, similar techniques may also provide insights about the evolution of chromosomes in other groups of animals or plants.
The paper, published in the journal G3: Genes, Genomes, Genetics, is entitled: "Lepidopteran Synteny Units (LSUs) reveal deep chromosomal conservation in butterflies and moths."
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