Science has built a reputation for breaking boundaries. Science never treads lightly along the great unexplored frontiers, whether those frontiers be space, sea, or any other object of wonder and speculation. Yet perhaps humanity’s most enduring curiosity resides in itself.
Whether one considers the human mind or the human body, no subject has remained as open…. or as mysterious. Psychology has challenged the complexities of human thought and cognition for over a century, but the physical workings—the basic building blocks—of individuals stood immersed in secrecy for centuries. Only in recent decades have the questions found a hint of an answer. Only recently have three simple letters transformed the way we view science, each other, and humanity as a collective whole. The discovery of DNA created a chain reaction which brought formerly alien terms such as genes and chromosomes into popular consciousness.
Today, due to the Human Genome Project, we know that each gene—and each chromosome— provides a vital link in our bodies’ proper functioning. Let us consider one chromosome— Chromosome 13—as a representative of humanity’s most basic building blocks.
History
A brief consideration of Chromosome 13’s history must necessarily begin with the birth of genetic science itself. Chromosomes were first discovered in the 1880s. Through this revolutionary finding, scientists eventually gained better insight into the structural makeup of DNA. Chromosomes exist in pairs, and each pair is connected by chemical bases (genes). Genes then produce a wide range of traits within individuals. Fifty years later, Barbara McClintock and Harriet Creighton pioneered work in genetic recombination (Berg and Singer 31). Chromosomal study (cytogenetics) truly broke ground in 1953, when Francis Crick and James Watson discovered the double helix structure in DNA. Three years later, scientists finally pinpointed the precise number of chromosomes in the human body—46. As scientists uncovered the basics of chromosome research, the next steps involved identifying individual chromosomes, studying abnormalities, and developing methods that would assist in both of these aims (“A History of the Human Genome Project,” 1195). The 1960s and 1970s brought important findings regarding chromosomal defects such as Down Syndrome, Edward’s Syndrome, and Patau Syndrome (the first discovered Chromosome 13-associated ailment). This era also witnessed the development of early banding techniques and interest in karyotyping (creating maps of individual chromosomes). (Gelehrter and Collins 87-88). In addition, Frederick Sanger introduced the world to the first sequenced genome in 1977 (“Chromosome 13,” Wellcome Trust Sanger Institute). The 1980s ushered in more advanced techniques, namely fluorescent in situ hybridization (FISH). (Billings and Brown 37) Also, Leroy Hood and Lloyd Smith developed society’s first automated sequencing machine. By 1990, scientists were more than ready for the next revolutionary step—a mapping of the entire human genetic profile. By all regards, the Human Genome Project is a resounding success, decoding over three billion nucleotides and identifying twenty-thousand plus genes in its short history (“A History of the Human Genome Project” 1195). Chromosomes 13 and 19 officially joined the ranks of the fully documented in 2004 (Winstead, “Two More Human Chromosomes”).
Analysis
Routine analysis of Chromosome 13 begins with banding. Banding exposes the various base pairs present on a chromosome by staining the chromosome with substances such as trypsin.
The three common banding techniques are Q-banding, G-banding, and R-banding. The former was the first method developed (using a fluorescent microscope), while G-banding is perhaps most plentiful today. R-banding utilizes heat and is ideal for staining the ends of chromosomes. Chromosome samples can be obtained from a variety of cell sources, including skin, organ tissues, blood, and amniotic fluid. Once the cells are obtained (typically around twenty), they are treated with an inhibitor substance which halts cell division and a solution which enlarges the cells, allowing more efficient analysis. Each chromosome reveals a unique banding pattern which assists with identification (Shaffer and Tommerup 121-123). When creating a karyotype, all chromosomes can be properly identified. (National Center for Biotechnology, “Genes and Disease”) Technology has promoted the rise of spectral karyotyping as well, a fluorescent technique which allows the simultaneous visualization of every chromosome pair in an organism (each identified by a different color). (Pitris, “Development”) An increased emphasis in DNA sequencing also contributed to the development of increasingly targeted and efficient sequencing machines—and a shotgun sequencing method— capable of delivering karyotypes on a large scale (Yablonsky 253-254). However, a primary aim of modern cytogenetics is the identification of abnormal chromosome issues. Abnormalities detected on a chromosome are labeled by chromosome number and the respective “arm” of the chromosome (the short arm of a chromosome is labeled ‘p’ and the long arm ‘q’). Therefore, genetic testing and karyotyping is a strong tool in medical communities specializing in pregnancy and oncology (Billings and Brown 34). Microarray technology and its use of high resolution techniques has become an important consideration in clinical karyotyping (“Couples Accept Prenatal Genetic
Testing,” 23-24).
Abnormalities on Chromosome 13 (or any chromosome) fall into two major categories: numerical and structural. Typical human cells hold approximately 46 chromosomes, with 22 regular pairs and two sex cells. Aneuploidy is the technical term for chromosomal number issues, and such conditions indicate either an absence of one of the traditional two chromosome pairs (monosomy) or a presence of extra chromosomes (trisomy). (Berg and Singer 89-91) Numerical abnormalities can occur after birth, but many chromosomal issues occur during gamete formation–resulting from meiosis (cell division) nondisjunction (the chromosome pairs do not separate). (Osoegawa 485-487) Most often, failure of the cellular “checkpoints” happens in older persons, thus the greater need for genetic testing for late-in-life pregnancies. Unfortunately, in cases of both monosomy and trisomy, survival rates for the afflicted remain low (“Couples Accept Prenatal Genetic Testing” 24). Chromosome number changes can take place in all cells or just a selected few. If only a few cell populations are affected (and cellular division errors are not contained in sex cells), the condition is known as chromosomal mosaicism (Gilbert 93).
Structural abnormalities encompass several problems: translocation, deletion, duplication, inversion. Structural issues arise during the process of homologous recombination, in which paired chromosomes exchange DNA information. This process involves the breaking and reconnecting of chromosome regions. Although chromosomes usually align and exchange information from regions with matching sequences, crossover can sometimes create alignments and exchanges which are not matched (translocation). Deletions, on the other hand, indicate that part of a chromosome (ranging from a few nucleotides to an entire piece) is missing, while duplications signal extra regions of DNA and genes on a chromosome. Finally, when a chromosome breaks and rearranges (reverses) itself, inversion has occurred. Any of these abnormalities can cause a wide range of physical and mental difficulties within an afflicted individual (National Center for Biotechnology, “Genes and Disease”). In addition, both structural and numerical abnormalities can result from a secondary source such as cancer. These types of conditions are acquired, whereas constitutional conditions are present from birth (Yablonsky 255).
Structure
Chromosome 13 is a paradox. Although it represents the largest acrocentric (with only one gene-coding arm) chromosome, the bountiful chromosome possesses the lowest gene density.
In April of 2004, the Wellcome Trust Sanger Institute mapped the entire sequence of the chromosome. The institute’s findings were published in Nature, and highlighted some important characteristics of the newly mapped chromosome: 95,567,076 base pairs, 633 gene structures, 296 pseudogenes, and 105 RNA genes. Research head Andy Dunham characterized the chromosome’s puzzling lack of density with the following statement: “Chromosome 13 has a dramatic genomic landscape, in the centre of which is a huge ‘desert’ of only 47 genes. Normally we would expect about 180 genes in such a region of DNA” (“Human Chromosome 13,” Wellcome Trust Sanger Institute). The centromere of Chromosome 13 rests close to its edge, as is the case with most acrocentric chromosomes. This positioning causes the shortness of the arms, and allows the centromere to be connected to small structures known as stalks or satellites.
Genes rest in these structures that code ribosomal RNA. Since the institute’s groundbreaking study, other researchers have concluded slightly differing figures, ranging number of genes anywhere between 300 and 700 and estimating base pairs figures as high as 113 million.
Whatever the true numbers may be, this important chromosome still accounts for roughly four percent of the human body’s DNA (Gilbert, “Chromosome 13”). The analysis also uncovered several genes and anomalies which may contribute to various diseases and conditions, including schizophrenia and breast cancer. Follow-up studies have also implicated Chromosome 13 in conditions ranging from autism to thrombophilia (“Possible Autism Gene,” 19).
Prominent Related Conditions
One of the most renowned (and most fatal) conditions associated with Chromosome 13 is retinoblastoma. A form of eye cancer, retinoblastoma causes tumor development in the portion of the eye dealing with color and light—the retina. A telling symptom for retinoblastoma is a noticeable whiteness present in the eye’s pupil. Poor vision, irritation, eye pain, and crossed eyes also serve as indicators of the condition (“Retinoblastoma,” The Merck Institute). Studies pinpoint retinoblastoma as a disease particularly prevalent among young children, due to the susceptibility of the immature retina present in children. An estimated 250 children are diagnosed with the condition each year, accounting for three percent of all childhood cancers. When untreated, the disease is almost always fatal, but early treatment increases odds of survival to a promising ninety percent (National Center for Biotechnology, “Genes and Disease”). Hereditary forms of retinoblastoma present the bleakest outlook, since multiple tumors in both eyes are a typical result, as is the development of a brain tumor known as pinealoma (Takahaski and Inoue 181).
Incidences of retinoblastoma are directly linked to a particular gene located on region 13q14 of Chromosome 13….the Rb1 gene. Since individuals can inherit mutations of this gene, genetic testing can indicate an individual at risk for developing the condition. Complete deletion of the gene (the most common non-hereditary form) can cause related physical and cognitive issues such as mental retardation, a broad, short nose, and ear defects. Whether mutations occur in this gene or the gene is victim to deletion, cells experience problems with halting DNA replication due to a lack of available functional protein (Takahaski and Inoue 179-180). If left unchecked, cells will replicate endlessly, leading to the inevitable formation of tumors. In this sense, retinoblastoma has aided scientists in understanding tumor origins. Since a lack of or elimination of Rb likely leads to cancer with retinoblastoma, scientists now theorize that the Rb gene’s role in cells is tumor suppression (National Center for Biotechnology, “Genes and Disease”). Such insight is vital as medical communities around the world continue the fight against cancer.
Structural issues can also afflict Chromosome 13. As mentioned earlier, the sixties and seventies era introduced the world to one if its first chromosome-based disorders, Patau Syndrome. The condition is also called Trisony 13, because every body cell contains three copies of Chromosome 13. Therefore, this syndrome is classified as a numerical abnormality.
However, some cases do exist in which translocation causes a portion of the chromosome to attach with another chromosome through rearrangement. Further, a few cases of Trisomy 13 exist in which just a few body cells are afflicted with an extra chromosome—Mosaic Trisomy 13 (“Trisomy 13 Syndrome,” WebMD).
Most often, nondisjunction of reproductive cells yields Trisomy 13. As such, if the affected reproductive cell is contributed to the child (especially by the mother), then the child will develop the condition. Similarly, Mosaic Trisomy 13 also results from unpredictable errors in cellular formation. The only type of the condition which may be inherited is Translocation Trisomy 13, due to the possibility that parents may be carriers of a genetic rearrangement between a separate chromosome and Chromosome 13. Although such individuals do not express symptoms of the syndrome, their children do hold a much higher risk of developing the condition
(“What is Trisomy 13?”, Living).
What are the primary symptoms of Trisomy 13? Like many numerical abnormalities, extreme mental retardation is perhaps the most prevalent indication of the disorder. Accompanying physical defects include hypotonia (weak muscle tone), a cleft (open) palate or lip, small eyes, coloborna (split in the iris of the eye), and skeletal development difficulties.
Indiividuals diagnosed with Trisomy 13 are also more vulnerable to serious medical conditions, particularly heart defects (“Trisomy 13 Syndrome,” WebMD). Tragically, the seriousness of the disorder produces a low mortality rate. Precious few cases live to see a first birthday, and at leas one half pass away within a month of birth. Although Trisomy 13 is relatively rare (affecting in 5000 births), (“What is Trisomy 13?”, Living) genetic counseling and genetic testing can shed important light on the issues facing an afflicted individual. Chromosome 13 and its related conditions remind us of the importance of progress.
Fifty years ago, individuals afflicted with diseases such as Trisomy 13 and Retinoblastoma would be dismissed as hopeless. Today’s genetic technologies are criticized by philosophers, economists, and even some members of the medical community. However, the millions of lives forewarned and even saved from debilitating, deadly disease speak a different story….as will the millions of future citizens now equipped with the necessary gear to travel confidently along humanity’s final unknown frontier
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