3 - Genoma Umano.

Il Genoma Umano contiene circa 20.000 geni.
Si tratta, qui, delle piccole sequenze che codificano le proteine.
Ma - si badi bene - questa parte codificante rappresenta solamente l'1,2% del genoma totale. Ciò - per differenza - significa che la quasi totalità, il 98,8% del DNA, è quella parte nota come "non codificante".
 Proprio quello che fu tacciato d'essere 'spazzatura', sospettato immediatamente di essere almeno un residuo inutile di precedenti versioni superate di DNA non più aggiornato, né necessario.

Oggi si va facendo sempre più spazio la teoria per la quale questo DNA 'non codificante' non sarebbe propriamente spazzatura: se da una parte è ancora piuttosto lontana la sua riabilitazione completa, tuttavia si comincia a pensare che almeno una parte di esso faccia qualche cosa di non solo utile, ma anche - e più correttamente - indispensabile per la sopravvivenza.

Si comincia a fare strada l'idea secondo cui alcune porzioni dell' EX DNA spazzatura assolvano compiti indispensabili al normale sviluppo fisico dell'essere vivente cui appartiene, dai primi stadi di uovo e poi d'embrione, fino a quello adulto. Il cattivo funzionamento di queste porzioni 'apparentemente silenti' (un termine molto più diplomatico, nevvero?) di DNA avrebbe effetti deleteri sull'individuo, determinando in ultima analisi deformità,, malfunzionamenti, cancro ed altro.

Ufficialmente, il termine 'DNA spazzatura' è caduto in disuso, come negli ultimi mesi hanno dichiarato apertamente anche i rappresentanti (Francis Collins) dell'Istituto Nazionale per la Sanità Statunitense.
Questa posizione implica anche di conseguenza - anche se nessuno lo dichiara onestamente in termini così chiari - che noi non abbiamo ancora capito completamente come funzioni il nostro DNA.

Facendo il paragone con un alfabeto non conosciuto, siamo al punto in cui crediamo di averne decifrato l'alfabeto forse per intero e magari anche qualche parola.
Ci si rende conto, così, che da questo stadio a quello di potere scrivere frasi di senso compiuto dovrà scorrere ancora un bel po' di acqua sotto i ponti. Nessuno si azzardi - quindi - a parlare di poesia o di letteratura!

Al momento, la situazione è la seguente:

1) Come non eravamo in grado di dire che il DNA non codificante non fosse funzionale, per cui non potevamo chiamarlo "spazzatura" (Junk DNA),

2) Esattamente nel medesimo modo non sappiamo bene ancora quale funzione/i esso possa avere.

3) Di conseguenza, sarà meglio non abbracciare alcuna teoria con troppo entusiasmo, per non produrre quella che poi - con dispiaciuta riluttanza - si dovrà eventualmente definire "cattiva scienza".

Sappiamo che errori del genere sono stati già commessi in passato: dovremmo imparare da essi e non ricaderci.
Un esempio è dato dalla sostituzione del finalismo religioso con la selezione naturale: per troppo entusiasmo, per un certo periodo si incorse in una ipercorrezione  che attribuiva tutto alla Selezione Naturale, persino contro il parere più convinto dei migliori biologi, che in alcuni dettagli non ammettevano un meccanismo adattivo (di adattamento all'ambiente).

L'opinione di questi biologi - in parole povere - è che un genoma pienamente efficiente (senza DNA silente) non sarebbe affatto coerente con il fatto che ciascuna Specie ebbe ad evolversi attraverso ere di casualità e di false partenze.

Migliaia di nuove variazioni del genoma

Thousands 

of never-before-seen 

human genome variations 

uncovered 

 Thousands of never-before-seen genetic variants in the human genome have been uncovered using a new genome sequencing technology.

 These discoveries close many human genome mapping gaps that have long resisted sequencing.

New technology is closing many human genome mapping gaps that have  long resisted sequencing [Credit: Thinkstock] 

The technique, called single-molecule, real-time DNA sequencing (SMRT), may now make it possible for researchers to identify potential genetic mutations behind many conditions whose genetic causes have long eluded scientists, said Evan Eichler, professor of genome sciences at the University of Washington, who led the team that conducted the study. 

"We now have access to a whole new realm of genetic variation that was opaque to us before," Eichler said. 
Eichler and his colleague report their findings Nov. 10 in the journal Nature. 
To date, scientists have been able to identify the genetic causes of only about half of inherited conditions. 
This puzzle has been called the "missing heritability problem." 
One reason for this problem may be that standard genome sequencing technologies cannot map many parts of the genome precisely. 
These approaches map genomes by aligning hundreds of millions of small, overlapping snippets of DNA, typically about 100 bases long, and then analyzing their DNA sequences to construct a map of the genome. 
This approach has successfully pinpointed millions of small variations in the human genome. 
These variations arise from substitution of a single nucleotide base, called a single-nucleotide polymorphisms or SNP. 
The standard approach also made it possible to identify very large variations, typically involving segments of DNA that are 5,000 bases long or longer.

But for technical reasons, scientists had previously not been able to reliably detect variations whose lengths are in between—those ranging from about 50 to 5,000 bases in length.

The SMRT technology used in the new study makes it possible to sequence and read DNA segments longer than 5,000 bases, far longer than standard gene sequencing technology. This "long-read" technique, developed by Pacific Biosciences of California, Inc. of Menlo Park, Calif., allowed the researchers to create a much higher resolution structural variation map of the genome than has previously been achieved. 
Mark Chaisson, a postdoctoral fellow in Eichler's lab and lead author on the study, developed the method that made it possible to detect structural variants at the base pair resolution using this data. 
To simplify their analysis, the researchers used the genome from a hydatidiform mole, an abnormal growth caused when a sperm fertilizes an egg that lacks the DNA from the mother. 
The fact that mole genome contains only one copy of each gene, instead of the two copies that exist in a normal cell simplifies the search for genetic variation. 
Using the new approach in the hydatidiform genome, the researchers were able to identify and sequence 26,079 segments that were different from a standard human reference genome used in genome research. 
Most of these variants, about 22,000, have never been reported before, Eichler said. "These findings suggest that there is a lot of variation we are missing," he said. 

The technique also allowed Eichler and his colleagues to map some of the more than 160 segments of the genome, called euchromatic gaps, that have defied previous sequencing attempts. 
Their efforts closed 50 of the gaps and narrowed 40 others. 
The gaps include some important sequences, Eichler said, including parts of genes and regulatory elements that help control gene expression. 
Some of the DNA segments within the gaps show signatures that are known to be toxic to Escherichia coli, the bacteria that is commonly used in some genome sequencing processes. Eichler said, "It is likely that if a sequence of this DNA were put into an E. coli, the bacteria would delete the DNA." 

This may explain why it could not be sequenced using standard approaches.

He added that the gaps also carry complex sequences that are not well reproduced by standard sequencing technologies. 
"The sequences vary extensively between people and are likely hotspots of genetic instability," he explained. 
For now, SMRT technology will remain a research tool because of its high cost, about $100,000 per genome. 
Eichler predicted, "In five years there might be a long-read sequence technology that will allow clinical laboratories to sequence a patient's chromosomes from tip to tip and say, 'Yes, you have about three to four million SNPs and insertions deletions but you also have approximately 30,000-40,000 structural variants. 
Of these, a few structural variants and a few SNPs are the reason why you're susceptible to this disease.' Knowing all the variation is going to be a game changer." 

Source: University of Washington [November 10, 2014]

Genoma dei Latino-Americani e DNA nascosto.

Latino genomes reveal hidden DNA

Genoma dei Latino-Americani e DNA

nascosto.

Hidden in the tangled, repetitious folds of DNA structures called centromeres, researchers from Harvard Medical School and the Broad Institute have discovered the hiding place of 20 million base pairs of genetic sequence, finding a home for 10 percent of the DNA that is thought to be missing from the standard reference map of the human genome.

Twenty million missing base pairs of DNA mapped to previously uncharted
regions of the human genome [Credit: iStock]

Mathematician Giulio Genovese, a computational biologist in genetics at HMS and at the Broad Institute, working in the lab of geneticist Steven McCarroll, HMS assistant professor of genetics and director of genetics for the Stanley Center for Psychiatric Research at the Broad Institute, found a way to use the genomes of Latinos to interpolate the locations of these missing pieces. Their findings were published in The American Journal of Human Genetics on August 8.
“In nature, polymerase, the molecular machinery that copies DNA within living cells, can sequence hundreds of millions of base pairs of DNA. The techniques we’ve developed to sequence DNA in the lab can only do relatively short segments, and we need to stitch those pieces together after the fact,” Genovese said. “So while we wait for sequencing technology to catch up with nature, we wanted to see if we could use mathematical patterns to find a place for some of the missing pieces.”
By using the genomes of admixed populations—populations, such as Latinos and African Americans that derive ancestry from more than one continent—the team developed a sophisticated mathematical method to help fill in the uncharted regions on the human genome map. The map is a key tool that geneticists rely on to find disease genes and identify the functional genetic variations at the core of human diversity. The unmapped DNA also sometimes resembles known, mapped genes, which can interfere in attempts to study similar sequences.

Best known as the molecular hinges that help chromosomes divide, centromeres have been widely considered structural elements that were unlikely to harbor protein-coding genes, the researchers said. For this reason, their finding—that nearly half of the unmapped sequences contained in available genomic reference libraries, including many protein-coding genes, were located in the centromeres—was unexpected.
Insight from a diverse population
Surprisingly, the study also found that the genomes of Latino individuals are a uniquely powerful resource for assembling maps of the human genome. The study searched 242 Latino genomes from the 1000 Genomes Project Phase 1 for DNA sequences that have not yet been located on the reference human genome map.
“Throughout the history of genomic research, different populations have given unique gifts to genetic inquiry because of the history or structure of that population,” said McCarroll.
The power of the Latino genome for Genovese’s approach came from the contribution of the African ancestors that many Latino individuals have. Because of the long history of human evolution on the continent, the African genome is rich in genetic diversity. Other human populations evolved from subsets of that diverse population, as small groups migrated around the globe just a few tens of thousands of years ago. (Sometimes, however, the lack of diversity in a population can be an asset for researchers. There are island populations that have allowed the discovery of recessive mutations that are rare in most of the world, but happen to be more common on a given island.)
“Latino populations have a relatively distinctive gift to give. Having some recent African ancestry, but just a little, can yield especially powerful information about what the structure of the human genome is in all populations,” McCarroll said.  
When chromosomes recombine with each other in each generation, they do so in relatively large segments or chunks. In the genomes of Latinos— many of whom trace ancestry to European, Native American and African populations—the mixed European, Native American and African sequences form a mosaic of large segments.
Imagined as separate colors, an admixed genome would look like a mosaic with large red, green and blue tiles, rather than a video screen with tiny, mixed-color pixels.
Genovese developed an algorithm that could use a missing sequence’s proximity to known genetic markers to pinpoint where on the chromosome the missing pieces fit—a technique first reported in a related paper in February, which localized a smaller sample of genes.
The technique works best when individuals have some African DNA because the diversity among African genomes provides a high number of genetic markers. But Genovese discovered that his technique is most powerful when individuals have only a little African ancestry— because this genetic “signal” is then most localized to a small number of regions in their genomes. Because the sampled Latino genomes had low levels of African ancestry (on average, just a few percent, compared to around 80 percent in African Americans), it was more powerful for pinpointing where on the map the marker was.
The blank spots on the map that the researchers identified were the centromeres, the only places where the missing DNA could be hidden.
A new approach to mapping
Until this work, scientists have tended to assume that mapping the remaining patches of terra incognita in the human genome would require future improvements in sequencing technology.
“I think people have tended to assume that someone will invent some sequencing technology that can magically read chromosomes in sequence from end to end,” McCarroll said. “Giulio approaches the problem as a mathematician, and his favorite genome technology is his own mind—he saw a way to answer this question using data that was already in front of us, looking for patterns and relationships in the data instead of trying to sequence everything.”
The highly repetitive DNA that makes up much of the centromeres is especially challenging to sequence with current technology. Instead of trying to sequence all the way through the unknown regions, the researchers used known information on both sides of the gaps to show what fits in the middle.  
The millions of base pairs of sequence that Genovese and McCarroll’s team have located will be added to the next release of the reference human genome assembly—the “Google maps” of the human genome that geneticists use every day—providing a more comprehensive view of the genome and how the pieces all fit together.

Author: Jake Miller | Source: Harvard Medical School [August 08, 2013]