Genetics, Chromosomes

Development

W. Waldeyer coined the term "chromosome" in 1888. Sexual chromosomes are essential in development. The sexual organs that will develop will depend on the presence or absence of the Y chromosome in the cells of the embryo. With a Y chromosome, the embryo will become a boy, while with two Xs, a girl will grow.

We can find many different chromosomes. Chromosome 1 is the largest of the human chromosomes, made up of approximately 249 million base pairs of the nucleotide, and accounts for approximately 8% of the entire DNA within a human cell.

By convention, chromosomes are numbered based on the quantity of nucleotides present (size):

• Chromosome 2 with about 243 million nucleotides
• Chromosome 3 is the third largest and has nearly 200 million nucleotides.
• Chromosome 4 has approximately 192 million nucleotides
• Chromosome 5 with 181 million nucleotides
• Chromosome 6 with about 170 million nucleotides
• Chromosome 7 with about 158 million nucleotides
• Chromosome 8 has over 146 million nucleotides
• Chromosome 9 has over 140 million nucleotides
• Chromosome 10 has about 135 million nucleotides
• Chromosome 11 has just under 135 million nucleotides
• Chromosome 12 has approximately 132 million nucleotides
• Chromosome 13 has about 114 million nucleotides
• Chromosome 14 has approximately 106 million nucleotides
• Chromosome 15 has around 100 million nucleotides
• Chromosome 16 has approximately 89 million nucleotides
• Chromosome 17 has approximately 79 million nucleotides
• Chromosome 18 has about 76 million nucleotides
• Chromosome 19 has nearly 64 million nucleotides
• Chromosome 20 has approximately 62 million nucleotides
• Chromosome 21 has approximately 47 million nucleotides
• Chromosome 22 has approximately 50 million nucleotides

Syndromes associated with changes in the structure or number of chromosomes in humans:

• Trisomy 2
• Trisomy 8
• Trisomy 9
• Trisomy 13
• Trisomy 16
• Trisomy 18
• Trisomy 21

Molecular Level

DNA is the biological molecule used by cells to store the cell's genetic information. The DNA molecule is made of nitrogenous bases, cytosine, and thymine, which are pyrimidines, and adenine, and guanine, which are purines. These strands of DNA are paired and form a double helix structure, in which the strands arrange in an antiparallel fashion. The antiparallel orientation of the strands means that the beginning 5' end of one strand's orientation is opposite the 3' end of the second strand, which is necessary for the eukaryotic DNA replication mechanism.[1]

These DNA strands then wrap around proteins called histones. The eight histone proteins are two of each of the following: H2A, H2B, H3, and H4. This structure of the DNA wrapped around the eight histone proteins is called a nucleosome. These nucleosome structures are related to each other via another histone protein, H1, which serves the function of further compacting the DNA material and creating a more complex chromatin structure called a solenoid. These solenoids then further form more complex structures via coiling to form supercoils, allowing for the formation of the structure known as the chromosome via specialized protein-protein interactions and intermolecular forces. A region called the centromere is a constriction in the middle of the chromosome. This region serves as an anchor point for joining sister chromatids and is also where the machinery attaches to separating chromatids during cell division and replication.[2][3][4]

Further exploring the structure of chromosomes, a chromosome can be characterized by the position of the centromere, resulting in telocentric, acrocentric, submetacentric, and metacentric chromosomes. Telocentric chromosomes classify as having the centromere at the terminal end of the arm of the chromosome. Due to this positioning, a shorter and longer arm is created; the shorter arm is referred to as the 'p' arm, and the longer arm is the 'q' arm. Acrocentric chromosomes are characterized by the centromere being very near the end of the chromosome, forming a very short p arm and long q arm. Submetacentric chromosomes have the centromere slightly away from the median, resulting in a slightly shorter p arm and minorly elongated q arm. Metacentric chromosomes have the centromere in the middle of the chromosome, with both arms nearly equal in length.[5]

An additional feature of eukaryotic chromosomes is telomeres. These are specialized structures at the end of DNA molecules and allow for continued replication to occur. They consist of many repeats on the 3' end of DNA molecules for stability and elongation. The replication machinery has the unfortunate consequence of losing genetic material from the 3' end in each replication cycle, as it is not able to replicate the entirety of a DNA strand, making the telomere essential to not losing genetic material that encodes for crucial proteins. Also, the telomerase enzyme allows for species-dependent terminal sequences to be added to the 3' end, allowing some protection against this inevitable loss of the end of the DNA sequence.[6]

Chromosomes can exist in the previously described tightly packed structure, referred to as heterochromatin, in which methylation of the DNA and other intermolecular forces keep the structure coiled and condensed. For transcription to occur with RNA polymerase and the other required proteins, the tight heterochromatin structure must unwrap to allow the transcription machinery to access the DNA strands. This looser structure with accessible DNA is referred to as euchromatin.[7][8]

When describing how many chromosomes are present within a cell, the cell type will determine how many copies of the chromosomes are present. For example, in a human somatic cell, there are 46 total chromosomes, or 23 pairs of chromosomes, in which each pair has one copy of the chromosome from the mother and the second copy from the father. Of the 23 pairs, 22 are autosomal chromosomes, and the last pair are the sex chromosomes. In autosomal chromosomes, these individual chromosomes are homologous as they contain genes that encode for similar traits. These somatic cells are referred to as diploid cells because they contain these homologous pairs within the nucleus. In contrast, haploid cells do not contain these pairs and only contain one set of chromosomes. Examples of haploid cells include germs cells such as sperm and ova. The sex chromosomes are X and Y, with the possible pairs being XX in females and XY in males. The Y chromosome is smaller in size compared to the X chromosome and contains specific genes whose products confer 'maleness' to the being, for example, the SRY gene. Traits encoded on the X chromosome are referred to as X-linked, and females can be homozygous dominant, homozygous recessive, or heterozygous due to the XX genotype. In contrast, males can only be the hemizygous genotype due to the XY genotype. [9]

During cell division and replication, the chromosomes within the cell undergo a variety of changes to form a new identical cell. Various morphologies of the chromosome can be examined in the metaphase and anaphase portions of cell division, as the chromosomes assume a tightly contracted configuration during these phases. Prior to mitosis, the chromosomes duplicate themselves and form pairs of the genetic material. At the beginning of the cell division process, in the prophase, the chromosomal genetic material is in the early stage of condensation. During metaphase, the chromosomes align in the middle of the cell, consisting of two sister chromatids. These sister chromatids are attached to each other by the centromere, and this is the anchor point at which two chromatids become separated during anaphase as the individual chromatids move to opposite poles. After telophase and cytokinesis, the resulting two cells will have the same structures and number of chromosomes as the original parent cell.[10]

Testing

The literature references many tests capable of identifying the cause of the non-physiological alteration of a structure before the disease develops or forensically to understand the causes.

Pathophysiology

• Mosaic trisomy 2 characterized by a highly variable phenotype
• Sindrome di Warkany 2 o trisomy 8
• Trisomy 9 presents several non-physiological abnormalities, including Coffin-Siris syndrome and malformation of Dandy-Walker
• Patau syndrome or trisomy 13
• 16p13.3 microduplication syndrome
• Edwards syndrome or trisomy 18
• Down syndrome or trisomy 21
• 22q11.2 microduplication syndrome

Clinical Significance

Throughout the DNA replication and mitosis process, there are many points in this cycle at which errors can occur, such as duplications, deletions, or translocations of whole chromosomes or parts of chromosomes, or failure of a chromosome to migrate to a particular pole, resulting in aneuploidies such trisomy 21 and Turner syndrome.[11]