Thursday, September 19, 2013

Recombinomics: Bisha_1 Recombinant Unwinds MERS Molecular Clock

September 18, 2013
The Kingdom of Saudi Arabia Ministry of Health (KSA-MoH) has released 45 sequences (accession numbers KF600612-KF600656) from MERS cases in 2012 and 2013 (see list here), which includes 13 full sequences (each of more than 30,000 BP).  The sequences reveal dramatic examples of recombination lead to rapid MERS evolution and adaption.

The earliest sequence, Bisha_1_2012, is from the first confirmed case (60M), which was also the source for EMC/12.  Bisha_1/2012 was from a sample collected June 19, 2012, while EMC/12 was from a sample collected June 13, 2012.  Although both samples were from the same patient and collected less than a week apart, the sequences were dramatically different.  The EMC/12 sequence was the first sequence made public and was related to the sequence from the earliest sequence, which was from a nurse in Jordan, Jordan-N3.  These two sequences for a distinct sub-clade that had shared polymorphisms clustered in the ORF1ab gene signaling recombination.  The other public sequences were easily distinguished from this sub-clade, and these differences were used to general a molecular clock suggesting MERS was evolving quickly and had recently infected humans.

However, this type of analysis assumes that the polymorphisms are acquired at a steady rate, but the clustering suggested the differences were due to recombination and therefore not useful for calibrating a molecular clock and predicting an interspecies jump to humans.  The Besha_1/2012 sequence however was closely related to the more recent sequences, suggesting the patient was infected by at least two very distinct MERS coronavirus.

Moreover, the Bisha sequence had clear evidence supporting additional recombination within this second sub-clade.  The polymorphisms in the 5’ end of the genome (positions 11492-22790) had 7 polymorphisms found in England1 (from Qatari, 49M. who was transported to England by air ambulance and placed on life support for 9 months prior to death), while the 3’ end of the genome (positions 23648-29850) had 9 polymorphism found in the first four sequences from Al Hasa (Al Hasa_1,Al Hasa_2, Al Hasa_3, Al Hasa_4).

The clustering of these shared polymorphism signals evolution by homologous recombination.

However, the sequences from a case in Al Batin (Hafr-Al-Batin_1_2013), collected on June 4, 2013 had even more dramatic examples of recombination, including clustered polymorphisms from Jordan-N3 (positions 542-1833) as well as additional clusters involving polymorphisms from Al Hasa, UAE, and England 1). 

The examples of extensive recombination in Al Batin, raises serious concerns about the rate of evolution involving multiple parental sequences.

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