Genetic predisposition to a severe clinical course of Covid-19 patients if they carry the allele HLA-C*04-01

Article in EClinicalMedicine:

Increased risk of severe clinical course of Covid-19 n carriers of HLA-C*04:01

 https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00379-5/fulltextA

Indus Valley Civilisation IVC population spoke a Proto-Dravidian language

Article by Bahata Ansumali Mukhopadhyay

Ancestral Dravidian languages in Indus Civilization: ultraconserved Dravidian tooth-word reveals deep linguistic ancestry and supports genetics 

reveals that the IVC population spoke a proto-Dravidian language. This research corroborates the findings of David Reich et al. that the IVC population were a mixture of Iranian migrants from the Zagros and the local Onge-related people. They could not have spoken Sanskrit because this language was brought by the Steppe population Yamnaya / Sinthasta and were unrelated to IVC.

https://www.nature.com/articles/s41599-021-00868-w

FROM DNA TO CHROMOSOMES: CONNECTING THE DOTS

 DNA or deoxyribonucleic acid is the hereditary molecule in all living cells. It is the blueprint for life that is made up of two strands attached together as a double helix. It consists of four nucleotides made up of a base, sugar and phosphate; the bases are adenine (A), cytosine (C), guanine (G), and thymine (T), shortened to ACGT.

Cells are the smallest structural units of living matter and consist of a nucleus and organelles that perform essential tasks that keep the cells alive. Plants and trees, fish, animals, and of course humans consist of an enormous number of cells coordinating with one another. We also know of the existence of single cell organisms such as yeast or bateria. A well studied unicellular organism is the microbe amoeba.

Genes are made of DNA and contain enough DNA to code for one protein. Specific genes launch instructions to make molecules known as proteins. We also possess genes that do no perform this function.

Proteins are large, complex molecules , the “workers” that do most of the work in cells and are required for the structure, function, and regulation of the body’s tissues and organs. They consist of hundreds or thousands of smaller units called amino acids, which are attached to one another in long chains. There are 20 different types of amino acids that can be combined to make a protein. The sequence of amino acids determines each protein’s unique 3-dimensional structure and its specific function.

The DNA contains the code of instructions on how and which proteins have to be made but it does not leave the cell. DNA delegates this task to the ribonucleic acid RNA.

The process of the making of a protein is complex and involves two major steps: transcription and translation that together are called gene expression. During transcription, the double strand or double helix of the gene’s DNA unzips itself and passes the information that is stored in each of the strands to RNA in the cell nucleus; this information is a copy of the strands of the DNA of a gene. The RNA that now contains the information for making the protein is called messenger RNA or mRNA because it carries the message from the DNA out of the nucleus to the cytoplasm of the cell; cytoplasm is a thick solution that fills each cell and is enclosed by the cell membrane. The second step occurs in the cytoplasm. It is here that the mRNA interacts with the ribosome that reads the sequence or genetic code of the mRNA nucleotide. Ribosomes are particles consisting of RNA and associated proteins that function to synthesize proteins and are therefore called protein factories. A sequence of three nucleotides, called a codon, usually codes for one particular amino acid. A type of RNA called transfer RNA (tRNA) assembles the protein, one amino acid at a time. Protein assembly continues until the ribosome encounters a “stop” codon (a sequence of three nucleotides that does not code for an amino acid).

The flow of information from DNA to RNA to proteins is one of the fundamental principles of molecular biology. It is so important that it is sometimes called the “central dogma.”

There are three main differences between DNA and RNA. The DNA is double stranded whereas the RNA is single stranded. A second major difference is that the DNA’s thymine is replaced by uracil in RNA. Thymine makes the DNA more stable whereas uracil requires less energy to maintain than thymine. The third difference is that DNA contains the sugar deoxyribose, while RNA has the sugar ribose. 

The sum total of an organism's DNA is called a genome. 

Genetics studies how individual genes or groups of genes are involved in health and disease.

In Genetic Genealogy, we combine a genetic analysis with genealogical research such as a traditional family tree, to study and understand family history. It is used in forensics to identify the DNA of an individual and link that person to a family, a missing person, or even a criminal.

The ultimate source of all genetic variation is mutation. 

Mutation is important as the first step of evolution because it creates a new DNA sequence for a particular gene, creating a new allele. Recombination also can create a new DNA sequence (a new allele) for a specific gene through intragenic recombination. Mutations are irreversible which is why  they can be passed on to the next generation.

The four classes of mutations are (1) spontaneous mutations (molecular decay), (2) mutations due to an error in replication (3) errors introduced during DNA repair, and (4) induced mutations caused by mutagens i.e. agents that cause a mutation.

Migration is determined by tracking the movement of specific alleles. This is what the National Geographic’s Genographic project set out to do on a global scale and has now expanded to numerous other projects by different companies.  Migration can also be estimated indirectly by assessing the extent of genetic differentiation among subpopulations.

A haplotype is a group of alleles that are inherited together from a single parent whereas a haplogroup is a group of similar haplotypes that share a common ancestor. In other words, a haplogroup is a combination of alleles at different chromosomal regions that are closely linked and that tend to be inherited together. As a haplogroup consists of similar haplotypes, it is usually possible to predict a haplogroup from haplotypes.

In human genetics, the haplogroups most commonly studied are Y-chromosome (Y-DNA) representing the patrilinieal line and mitochondrial DNA (mtDNA) representing the matrilineal line. 

DNA is located in the nucleus of cells in chromosomes and in smaller amounts in mitochondria. Humans possess about 25 thousand genes that as we have seen earlier are together called a genome i.e. the total sum of an organism’s DNA. A genome is thus the instruction manual that contains genetic information in about 3 billion bases. It is this instruction manual that ensures that humans can only produce human babies and elephants can only produce baby elephants.

A chromosome is made up of a single DNA strand or helix on which the genes are located. Humans have 23 pairs of chromosomes, one strand from each parent with a total of 46.

22 of the chromosomes are similar and are known as autosomal whereas the 23rd pair of chromosomes differs between men and women. In women, these chromosomes are similar and shaped like an X, the chromosomal pair is an XX. The two chromosomes in men are shaped as an X and a Y, the chromosomal pair is an XY. In addition to to Y-DNA and mtDNA analyses, autosomal DNA i.e. an analysis of the 22 analogous chromosomes can also be routinely carried out.

To summarise: DNA that contain the code for a specific protein are located in our genes and the genes are located in our chromosomes.

Article from BBC News on how a combination of DNA analysis and DNA matches from GEDmatch is solving cold cases.

A very interesting MUST READ article on how cold cases are being solved from DNA analysis and GEDmatch DNA matches to build genealogical trees that lead to the culprit:

https://www.bbc.com/news/technology-57801794

TRIANGULATION: WHAT IT IS AND WHAT IT IS NOT

Triangulation

There is a lot of confusion on what triangulation means as well as its purpose.

Some experts claim that when three people show DNA matches, they are an example of triangulation. 

Other experts state that the three individuals must share DNA on the same segment of the chromosome. This last statement is very important because triangulated segments are probably inherited from a common ancestor. Triangulation can also involve more than three individuals, but the minimum number is obviously three.

Triangulated matches that are not on the same segment could have been inherited from different ancestors that are not common to the three individuals who are being compared.

We must remember that it is possible to share a small amount of DNA with someone and not be related. For example, I share a very small amount of DNA with Neanderthals just like millions of other individuals but I am not related either to a Neanderthal nor to the millions of other people who share Neanderthal DNA.

The link below from GEDmatch explains triangulation very well with examples and could be helpful to understand the concept:

https://dna-explained.com/2020/01/23/triangulation-in-action-at-gedmatch/

Roopkund Lake's mysterious skeletons: mystery partially but not completely solved

Roopkund Lake’s mysterious skeletons: mystery partially but not completely solved by geneticists

Located at 5029 metres above sea level in the Himalayas, Roopkund Lake is a high altitude glacial lake situated in the Indian state of Uttarakhand. The lake is frozen in winter but when the snow melts, hundreds of skeletons of unknown origin are visible at the bottom of the lake and many artifacts have been found in the area.

A popular trekking, pilgrimage and tourist destination, visitors have removed many of the artifacts as souvenirs and conservationists fear that the precious remains that are shrouded in mystery will soon disappear. Details can be found in Wikipedia:  https://en.wikipedia.org/wiki/Roopkund

“Local legend says that the King of Kanauj, Raja Jasdhaval, with his pregnant wife, Rani Balampa, their servants, a dance troupe and others went on a pilgrimage to Nanda Devi shrine, and the group faced a storm with large hailstones, from which the entire party perished near Roopkund Lake” (cf. Wikipedia). Nanda Devi did not approve of their inappropriate celebratory behaviour and therefore punished them with death.

A team of geneticists led by David Reich, Kumarasamy Thangaraj and Niraj Rai have studied the DNA of several skeletons to try to understand their origin and the circumstances that led to their demise at Roopkund. They also carried out table isotope measurements, radiocarbon dating and oeteological analysis on the remains of the individuals.(https://www.academia.edu/40159432Ancient_DNA_from_the_skeletons_of_Roopkund_Lake_reveals_Mediterranean_migrants_in_India?email_work_card=title)

The team found that the skeletons did not result from a single event as would be expected from the local legend. They belonged to three different ancestries deposited there at different times approximately 1000 years apart:

• present-day South Asians dated to around 800 CE 7th -10th century (India, Pakistan, Nepal, Bhutan, Bangladesh)
• Eastern Mediterranean dated to around 1800 CE 17th-20th century (Primarily Crete, Mainland Greece)
• Southeast Asian dated also to around 1800 CE 17th -20th century (Primarily Malaysia, Vietnam)

The study says that the individuals were “broadly healthy” but 3 of them had unhealed compression fractures compatible with the violent hailstorms for which the region is known. The stature (height and robustness or gracile) of the analysed individuals is equally compatible with the ancestries identified from their DNA.  They included both males and females in similar proportions, thus excluding the possibility that the groups may have belonged to a military expedition: when discovered in 1942, the British feared that the skeletons belonged to a hidden Japanese invasion force.

The researchers also discovered that they belonged to a diverse group and not members of a single family.

The two main groups showed different dietary patterns, the South Asians exhibiting a more varied diet than the Eastern Mediterraneans.

Roopkund Lake lies on the Nanda Devi Raj Jat pilgrimage route. The pilgrimage today occurs every 12 years and date back to the 8th and 10th centuries as suggested by inscriptions in nearby temples. The authors therefore theorise that the skeletons of the South Asians dating back to the 7th-10th century belong to pilgrims caught in violent hailstorms. They suggest that the South East Asian skeletons also belong to this category.

The source of the skeletons belonging to Crete/Greece ancestry is a mystery. The authors propose that they “were born during the period of Ottoman political control. As suggested by their predominantly terrestrial, rather than marine-based diet, they may have lived in an inland location, eventually travelling to and dying in the Himalayas”. 

ARTICLE  https://doi.org/10.1038/s41467-019-11357-9 OPEN  Ancient DNA from the skeletons of Roopkund Lake reveals Mediterranean migrants in India  Éadaoin Harney1,2,3, Ayushi Nayak4,17, Nick Patterson5,6, Pramod Joglekar7, Veena Mushrif-Tripathy 7, Swapan Mallick3,5,8, Nadin Rohland3, Jakob Sedig 3, Nicole Adamski3,8, Rebecca Bernardos3, Nasreen Broomandkhoshbacht 3,8, Brendan J. Culleton9,10, Matthew Ferry3,8, Thomas K. Harper10, Megan Michel3,8,11, Jonas Oppenheimer3,8, Kristin Stewardson3,8, Zhao Zhang3, Harashawaradhana12, Maanwendra Singh Bartwal12, Sachin Kumar13,14, Subhash Chandra Diyundi 15, Patrick Roberts 4, Nicole Boivin4, Douglas J. Kennett16,17, Kumarasamy Thangaraj13,17, David Reich2,3,5,8,17 & Niraj Rai13,14,17  Situated at over 5,000 meters above sea level in the Himalayan Mountains, Roopkund Lake is home to the scattered skeletal remains of several hundred individuals of unknown origin. We report genome-wide ancient DNA for 38 skeletons from Roopkund Lake, and find that they cluster into three distinct groups. A group of 23 individuals have ancestry that falls within the range of variation of present-day South Asians. A further 14 have ancestry typical of the eastern Mediterranean. We also identify one individual with Southeast Asian-related ancestry. Radiocarbon dating indicates that these remains were not deposited simulta- neously. Instead, all of the individuals with South Asian-related ancestry date to ~800 CE (but with evidence of being deposited in more than one event), while all other individuals date to ~1800 CE. These differences are also reflected in stable isotope measurements, which reveal a distinct dietary profile for the two main groups.  NATURE COMMUNICATIONS | (2019)10:3670 | https://doi.org/10.1038/s41467-019-11357-9 | www.nature.com/naturecommunications 1

Nestled deep in the Himalayan mountains at 5029 m above sea level, Roopkund Lake is a small body of water (~40 m in diameter) that is colloquially referred to as Skeleton Lake due to the remains of several hundred ancient humans scattered around its shores (Fig. 1)1. Little is known about the origin of these skeletons, as they have never been subjected to systematic anthropological or archaeological scrutiny, in part due to the disturbed nature of the site, which is frequently affected by rockslides2, and which is often visited by local pilgrims and hikers who have manipulated the skeletons and removed many of the artifacts3. There have been multiple proposals to explain the origins of these skeletons. Local folklore describes a pilgrimage to the nearby shrine of the mountain goddess, Nanda Devi, undertaken by a king and queen and their many attendants, who —due to their inappropriate, celebratory behavior—were struck down by the wrath of Nanda Devi4. It has also been suggested that these are the remains of an army or group of merchants who were caught in a storm. Finally, it has been suggested that they were the victims of an epidemic5. 

To shed light on the origin of the skeletons of Roopkund, we analyzed their remains using a series of bioarcheological analyses, including ancient DNA, stable isotope dietary reconstruction, radiocarbon dating, and osteological analysis. We find that the Roopkund skeletons belong to three genetically distinct groups that were deposited during multiple events, separated in time by approximately 1000 years. These findings refute previous suggestions that the skeletons of Roopkund Lake were deposited in a single catastrophic event. 

 

ANCESTRAL NORTH INDIANS ANI: ORIGINS AND HISTORY OF Y DNA HAPLOGROUP R1a by Maciano Hays.

Based on brilliant genetics research, David Reich et al. discovered that migrants from the Steppes to the Indian sub-continent mixed with the population of the Indus Valley Civilisation (IVC) on the decline that they encountered to form the Ancient North Indian ANI population. The IVC population was itself a mixture of Iranians from the Zagros mountains and the local Onge-related people.

This paper by Maciano Hays describes succinctly the Indo-Iranian branch of the Y Haplogroup R1a to which the Steppe migrants to India belonged.

Please copy/paste the link below to your browser to open the file.

https://drive.google.com/file/d/1s_zuc6OHDUXy33XSQHY5R9LgRMAkv22g/view?usp=sharing