CELL, ORGANELLES, & DNA RESOURCES FOR TEACHERS, GENETIC GENEALOGIST AND YOU
Resource: Unlockinglifecode.org access 1/2018
Resource: Unlockinglifecode.org access 1/2018
A Genome Looks Like This
Visitors to the Genome exhibition are frequently intrigued by the Genome Ball, a three-dimensional model of the human genome that represents a creative synthesis of scientific knowledge and technical innovation. For students and adults raised on clinically produced karyotypes – those artificially arranged pairs of X-shaped chromosomes photographed during cell division – the Genome Ball will challenge all their previous (mis)conceptions and show the human genome in a new light.
How did we first begin to grasp the structure of the nucleus? It all began in 1682 when Anton van Leeuwenhoek, a fabric merchant in the Dutch city of Delft, examined blood cells of fish. Leeuwenhoek used a microscope with lenses he’d ground himself, and reported his observations in a letter to the Royal Society:
I came to observe the blood of a cod and of a salmon, which I also found to consist of hardly anything but oval figures … it seemed to me that some of them enclosed in a small space a little round body or globule …
If you’ve looked at human blood under a microscope, that description may sound odd: Mature red blood cells (RBCs) don’t contain nuclei – do they? You’re right! However, the RBCs of fish (and amphibians and reptiles) do indeed have nuclei, and Leeuwenhoek was the first to describe them. Nevertheless, the Royal Society wasn’t blown away by his letter (after all, how much could a business man with “little fortune and no formal education” know about science?). The “little round body or globule” remained nameless for the next 150 years.
Then, in 1831, the Scottish botanist Robert Brown was studying plant fertilization when he noticed that pollen moved in and out of “ovals” in the plant cells. He called each oval a “nucleus,” a Latin word meaning “nut” or “kernel” – a bit like a black walnut surrounded by its thick green hull. Not only did Brown’s name stick, but his 1833 paper even suggested that the nucleus was probably involved in fertilization and the development of embryos.
The next step in our nuclear narrative was taken by Friedrich Miescher, a Swiss physician who extracted and isolated a previously unknown substance from pus-soaked bandages at the hospital where he worked. White blood cells, a major constituent of pus, have very large nuclei, and Miescher correctly concluded that the substance came from those nuclei. He called it “nuclein.” Today we call it DNA.
Although the fine points of cell division were still unexplained, scientists in the early 1900s were eager to learn the number of chromosomes in human cells. However, counting the number of human chromosomes during cell division turned out to be quite a challenge. Even when chromosomes were lined up on the “midline” of a cell, scientists’ counts ranged from 16 to 36.
Evidently, Hans von Winiwarter got tired of these wide-ranging approximations. Using the best microscopes available to him in 1912, he produced early karyotypes by capturing and fixing human cells at the moment of cell division. Despite his best efforts, Winiwarter’s counts ranged from 46 to 49; and while noting correctly that women have two X chromosomes, he mistakenly concluded that males had only one X and no Y. For the next 40+ years, students were generally taught that human cells contained 48 chromosomes.
Finally, in 1956, the correct value of “46” was confirmed – 22 pairs of autosomes and 1 pair of sex chromosomes in human cells other than eggs or sperm. It’s surprising to learn that Watson & Crick had published their model of DNA’s structure, opening the world of modern genetics, several years before the number of human chromosomes was firmly established!
By the end of the 20th century, knowledge of DNA structure and the mechanisms of cell division had advanced dramatically. Yet, based on their school textbooks, most people still tended to picture chromosomes as the condensed “X-shaped” bodies seen in karyotypes. DNA was known to uncoil between cell divisions, but it was hard to imagine how such long straggling threads (more than 2 meters, or 6 feet, per cell) could pack into a nucleus only 6/1,000,000 of a meter in diameter (smaller than the diameter of a human hair).
Eventually, studies showed that DNA decreases in length when regions of about 166 base pairs wrap like twine around small proteins to form complexes known as nucleosomes . A short stretch of non-wound DNA falls between each nucleosomal unit, the result looking a bit like a string of beads. In such a configuration, a 1-meter (3-foot) strand of DNA is reduced to 14 cm (about 6 inches). This shortened strand then coils even more, until an X-shaped chromosome in a dividing cell measures roughly 1/10,000 the length of the DNA strand it contains!
So what does the 3-dimensional model of the nucleus, as seen in the Genome Ball, have to do with all this?
One of the most important discoveries in genome biology has been the demonstration that genomes are non-randomly organized in the nucleus.
Even though chromatin looks like long straggly threads, it is amazingly well organized: Thanks to the organized coiling of chromatin, genes are able to interact with the DNA regions that regulate them.
The genome is organized into “distinct regions of open and closed chromatin regulatory domains,” explains Dr. Laura Elnitski, senior investigator at the National Human Genome Research Institute (NHGRI) of the National Institutes of Health. Put more simply, chromatin that is less active in a given cell type, or chromosomes containing few genes, are located just inside the nuclear membrane; but more active chromatin (for example, a gene coding for insulin in healthy pancreatic cells), and chromosomes carrying many genes, occupy the center of the nucleus. Overall, the nuclear location of specific genes correlates with their activity in a given cell.
Erez Aiden (who spearheaded the Genome Ball project) also discussed chromatin organization in his prize-winning essay in Science: “Loci on the same chromosome – even at opposite ends – interact more than loci on different chromosomes.” And within individual chromosomes, “open [active] chromatin interacts more with open chromatin and closed with closed,” wrote Aiden. In short: Genes have more interactions with regions on their own chromosome; and within any given chromosome, active regions group together with other active regions, while quiet or gene-poor areas group with other quiet regions.
Aiden had found a paper theorizing that long polymers – DNA is a good example – are able to form very tight coils with no knots, “a configuration known as the fractal globule.” One of the most striking characteristics of the fractal globule is that it can be folded and refolded without disturbing the rest of the condensed polymer.
The fractal globule is easy to explain to graduate students because it closely resembles the only food we can afford: ramen, said Aiden.
Uncooked, the noodles don’t contain any knots. Even when partially cooked, they don’t get tangled in the cooking pan. However, ramen noodles do become tangled after cooking, whereas chromatin stably maintains its unknotted state throughout interphase – the period between cell divisions when chromatin in the nucleus uncoils. In that condensed but non-knotted configuration, sections of chromatin that are far apart on the long strands may be brought into proximity. Thus, interactions between chromatin on the same chromosome, or between sections with similar properties or functions, are made possible by the way chromatin is organized in the interphase nucleus.
These are but a few of the innovative and complex understandings that inspired the creators of the Genome Ball (for more information about the 3-D printing of the Genome Ball displayed at the exhibition, see the feature article “Super 3D Model: How the Genome Ball Was Created” on this website). Our knowledge of the nucleus has come a long way in the 332 years since Leeuwenhoek. But, as Aiden’s Science essay concluded: “at the fringes of our maps the world is full of surprises.”
The same is certainly true of the nucleus.
Source: Unlockinglifescode.org/the-genome-ball. Access November 19, 2017, Genome Project NIH
(2) “DNA packaging: Nucleosomes and Chromatin.” Nature Education 1 (2008):26.
(3) “Regulatory and Epigenetic Landscapes of Mammalian Genomes,” Current Topics in Genome Analysis 2014. March 26, 2014.
(4) “Leeuwenhoek Sees the Cell Nucleus.” Science of Aging: Timeline of Discoveries.
(5) Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome. Science 326 (9 October 2009): 189-324.
If you are frustrated or just need direction sin finding all those female ancestors with missing maiden names, or if you are not sure which Julia is your great-grandmother, you can look no further than the answers provided by mitochondrial DNA (mtDNA). One of the most powerful tools available to African-American genetic genealogists and African-American genealogists (new term genetealogy (ge-neh-tee-ol-0-gee), mtDNA offers a glimpse into the the maternal lines of even your most challenging ancestors. So how can mtDNA help you?
Each mitochondrion contains its own DNA and its own protein-synthesizing machinery. They reproduce by splitting in two after they make a second copy of the DNA. In humans, the mtDNA is in the form of a circle that contains approximately 16,500 nucleotide base pairs of DNA. (DNA molecules consist of two paired strands, and each strand is a long chain of four types of nucleotides, designated A, G, C and T.) In contrast, the DNA in the nucleus is divided into 46 linear chromosomes (23 from each of our parents) that have an average length of more than 200 million base pairs. Each person’s mitochondria come from the cytoplasm of the mother’s egg. The father’s sperm cells also contain mitochondria, but they are not inherited by his offspring.
Before people started to travel around the world, the rare changes that occurred in mtDNA over time resulted in unique types of mtDNA on every continent. Therefore, most contemporary mtDNAs can be assigned to a continent of origin based on the nucleotide sequence of the most variable region (Hypervariable control region HVRI) of the mtDNA. The HVRI region is about 400 base pairs in length and is the region where the mitochondria start making a new copy of their DNA. It is the region of the DNA molecule where mutations (changes) are most likely to occur. When a scientist determines the order of the four nucleotides in this region, they find a record of all of the mutations that have occurred over time as the mtDNA was passed from mother to daughter from generation to generation. These accumulated mutations are the basis for the unique types of mtDNA found on each continent. HVR2 is the second region and they both accumulate changes relatively quickly, and thus tend to be hype-variable from one person to the next unless those people are closely related. The third portion, the coding region (CR), accumulates far fewer changes and contains the nucleotide base pair sequence for mitochondrial genes.
Example: mtDNA Family Member
|Match ID||Type||Name||Matching segments on Chromosome 2||Overlap with previous match|
|1||F2||(A982870)||104323793 – 130334843 (24.045 cM)||New Root|
Within continents, regional mtDNA variation can be observed as well. When a woman’s mtDNA contains a new mutation, her descendants are likely to live near her. Therefore, a local area where she lived will be the only place in the world where this particular type of mtDNA is found. However, whenever people moved from one place to another they took their mtDNA with them. In sub-Saharan Africa, for example, there have been extensive movements of people over time. As such, a recent study has shown that approximately half of all African mtDNAs are shared among people from multiple countries in Africa. If an African-American has one of these shared mtDNAs, it is not possible to determine which country was the original home of the maternal ancestor who came to the U.S.
A second problem is that many African-Americans have a particular type of mtDNA that is clearly African in origin, but has not yet been observed among the African mtDNAs that have been analyzed. This situation occurs because there is an incredible amount of genetic diversity among Africans and African mtDNAs have not been studied extensively. In fact, the mtDNAs from many African ethnic groups have not been analyzed at all. Additional studies will help with this situation. However, if a particular mtDNA is rare enough to be found in only a small region of Africa, there is a good chance it will be difficult for researchers to find it. Some people suggest comparing these rare mtDNAs to similar mtDNAs that have already been found in Africa. However, when these comparisons are made, the rare mtDNA is usually similar to one of the common mtDNAs that are found in many countries. Therefore, it is not likely that a particular person’s mtDNA can be assigned to a particular country of origin. This conclusion is true not only for African mtDNAs, but also mtDNAs from every other continent as well.
Y-DNA| atDNA| Y-DNA Standards
Source: Scientific America, “How Do Researchers Trace Mitochondria DNA Over Centuries?” Digital Access 12/7/2016
National Institute of Health Genome Project, Digital Library, Cell Structure 2016